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CORK Bibliography: Drug Metabolism

103 citations. January 2005 to present

Prepared: March 2009

Acosta MC; Haller DL; Schnoll SH. Cocaine and stimulants. IN: Frances RJ; Miller SI; Mack AH, eds. Clinical Textbook of Addictive Disorders, 3rd edition. New York: Guilford Press, 2005. pp. 184-218. (135 refs.)

This is one of several chapters directed to a specific drug class. It begins with a brief review of use patterns, routes of administration, and metabolism, and pharmacology. There is also a review of medical complications, psychiatric comorbidity, prenatal drug exposure, and treatment approaches. The chapter concludes with a separate discussion of methamphetamine.

Ammon-Treiber S; Hollt V. Morphine-induced changes of gene expression in the brain. Addiction Biology 10(1): 81-89, 2005. (86 refs.)

Repeated opiate administration alters gene expression in different brain regions of rodents, an effect which may contribute to plastic changes associated with addictive behaviour. There is increasing evidence that multiple transcription factors are induced in morphine tolerance, sensitization and during morphine withdrawal. Whereas morphine treatment does not lead to major alterations in the expression of mu-opioid receptors (MOR), there is transcriptional regulation of proteins involved in iWOR trafficking such as GRK2 or beta arrestin 2 as well as altered expression of other receptors such as dopamine receptors, NMDA receptors, GABA(A) receptor and alpha(2A) adrenoceptor. Recent gene expression profiling studies reveal additional clusters of morphine-responsive genes: whereas single dose administration has been shown to predominantly, reduce expression of genes involved in metabolic function, ascending morphine doses leading to morphine tolerance revealed induction of genes which alter patterns of synaptic connectivity such as are or ania-3. These genes remained elevated after precipitated withdrawal, which also triggered the expression of several transcriptional activators and repressors. In addition, morphine has been shown to be a strong inducer of heat shock protein 70, a cell protective protein which might counter regulate opiate-induced neurotoxicity. Temporal expression profiles during a chronic morphine application schedule revealed discrete and fluctuating expression of gene clusters such as transcription factors, G-protein-coupled receptors and neuropeptides. Prolonged abstinence seems to be characterized by up-regulation of several transcription factors and persistent down-regulation of ligand gated ion channels such as glutamatergic and GABA-ergic receptor subunits. These long-term changes in receptor expression suggest a persistent alteration of synaptic signalling after morphine treatment.

Baker J; Jatlow P; Pade P; Ramakrishnan V; McCance-Katz EF. Acute cocaine responses following cocaethylene infusion. American Journal of Drug and Alcohol Abuse 33(4): 619-625, 2007. (8 refs.)

We report results of a randomized, double-blind, placebo-controlled, within-subject study (n = 8) to determine the ability of cocaethylene to modulate acute responses to cocaine and identify significant pharmacokinetic interactions between cocaine and cocaethylene. Stable plasma cocaethylene concentrations (0, 50, or 200 ng= ml) were maintained for 840 minutes. Cocaine (0, 0.25, or 0.5mg= kg) was injected over 1 minute after 240 minutes of cocaethylene. Blood samples, subjective, and physiological measures were collected. No differences over baseline responses were observed following 240 minutes of a steady state cocaethylene infusion for cardiovascular or subjective responses. " Rush'' duration following a cocaine challenge (0.5 mg= kg) declined when administered during the course of a 200 ng= mL cocaethylene infusion. (p 0.01). No pharmacokinetic interaction occurred when cocaine was administered in conjunction with cocaethylene. Findings indicate that continuous 8- hour exposure to cocaethylene is safe, produces acute tolerance to itself, and reduces some behavioral effects of coadministered cocaine. Agonist substitution therapy may have potential as an alternative treatment for cocaine dependence.

Bao ZP; He XY; Ding XX; Prabhu S; Hong JY. Metabolism of nicotine and cotinine by human cytochrome P450 2A13. Drug Metabolism and Disposition 33(2): 258-261, 2005. (27 refs.)

Nicotine, a major constituent of tobacco, plays a critical role in smoking addiction. In humans, nicotine is primarily metabolized to cotinine, which is further metabolized to trans-3'-hydroxycotinine. Recently, we have demonstrated that heterologously expressed human CYP2A13 is highly active in the metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a nicotine-derived carcinogen. In the present study, CYP2A13-catalyzed NNK metabolism was found to be inhibited competitively by nicotine and N'-nitrosonornicotine (NNN), suggesting that both nicotine and NNN are also substrates of CYP2A13. We have further demonstrated that human CYP2A13 is indeed an efficient enzyme in catalyzing C-oxidation of nicotine to form cotinine, with the apparent Km and V-max values of 20.2 muM and 8.7 pmol/min/pmol, respectively. CYP2A13 also catalyzes the 3'-hydroxylation of cotinine to form trans-3'-hydroxycotinine, with the apparent K-m and V-max values of 45.2 muM and 0.7 pmol/min/pmol, respectively. The importance of CYP2A13-catalyzed nicotine and cotinine metabolism in vivo remains to be determined.

Benetton SA; Fang C; Yang YO; Alok R; Year M; Lin CC; Yeh LT. P450 phenotyping of the metabolism of selegiline to desmethylselegiline and methamphetamine. Drug Metabolism and Pharmacokinetics 22(2): 78-87, 2007. (18 refs.)

Although there is evidence in the literature of the participation of CYP2B6 in the metabolism of selegiline, it is not clear which other CYP isofoms contribute to its metabolism. The aim of this study was to investigate the P450 isozymes (CYPs) involved in the metabolism of selegiline to desmethylselegiline (DMS) and methamphetamine (MA) using four assays: incubation of selegiline with cDNA expressed CYPs, inhibition of DMS and MA formations in human liver microsomes by CYP-selective chemical inhibitors or CYP-specific antibodies, and correlation analysis. Correlation analysis, performed in a bank of 15 individual human liver microsomes, yielded correlation coefficients for DMS and MA formation of 0.769 and 0.792, respectively, for CYP2136 (p < 0.0001) and 0.333 and 0.349, respectively, for CYP3A4 (p < 0.05). These results were supported by chemical /specific antibody inhibition assays. The results of correlation analysis and chemical inhibition also indicated that CYP2A6 seems to play a small role in the metabolism of selegiline. These findings confirm that CYP2136 plays a major role in the metabolism of selegiline and also suggest the involvement of CYP3A4 and CYP2A6.

Benowitz NL. Clinical pharmacology of nicotine: Implications for understanding, preventing, and treating tobacco addiction. Clinical Pharmacology and Therapeutics 83(4): 531-541, 2008. (50 refs.)

Understanding the basic and clinical pharmacology of nicotine provides a basis for improved prevention and treatment of tobacco addiction. nicotine acts on nicotinic cholinergic receptors in the brain to release dopamine and other neurotransmitters that sustain addiction. neuroadaptation and tolerance involve changes in both nicotinic receptors and neural plasticity. Nicotine addiction can occur in the context of physical dependence characterized by self-medication to modulate negative affect and/or to relieve withdrawal symptoms, as well as, in light or occasional smokers, primarily for positive reinforcement in specific situations. Nicotine is metabolized primarily by CYP2A6. its clearance exhibits considerable individual variability that is determined by genetic, racial, and hormonal (sex) factors. Genetically slow metabolism of nicotine appears to be associated with a lower level of dependence. Nicotine dependence is highly heritable and appears to be influenced by genes coding for some nicotine receptor subtypes, some neurotransmitter genes, and genes involved in neural connectivity. Novel pharmacotherapies for nicotine dependence include partial agonists for nicotinic receptors and nicotine vaccines. Pharmacogenetic studies suggest various candidate genes and a nicotine metabolism phenotype that influence outcome. human pharmacology studies of nicotine and smoking behavior also provide a basis for assessing the benefits and risks of long-term nicotine use for harm reduction and for a potential cigarette regulatory strategy that includes reducing nicotine content of cigarettes to nonaddictive levels.

Berlin I; Gasior MJ; Moolchan ET. Sex-based and hormonal contraception effects on the metabolism of nicotine among adolescent tobacco-dependent smokers. Nicotine & Tobacco Research 9(4): 493-498, 2007. (28 refs.)

Variations in nicotine metabolism influence smoking patterns. Differences between sexes or related to sex hormones may affect nicotine metabolism. Because smoking initiation starts during adolescence, observations gathered from adolescent smokers might broaden our understanding of such sex-based differences. We tested the hypothesis that nicotine metabolism-as indexed primarily by the ratio of trans-3'-hydroxycotinine (3HC) to cotinine-is more rapid among adolescent girl smokers compared with boys and that regular use of hormonal contraceptives influences nicotine and cotinine metabolism. We also hypothesized that more rapid nicotine metabolism is associated with higher nicotine dependence as indexed by smoking frequency and morning urgency. Plasma samples of nicotine, cotinine, and 3HC concentrations were obtained from 120 adolescents (36 boys). Plasma nicotine and cotinine concentrations were similar in boys and girls. Median plasma 3HC concentrations were 44.45 ng/ml for girls versus 35.74 ng/ml for boys (p=.025), and median plasma 3HC-cotinine ratios were significantly higher in girls than in boys (0.317 vs. 0.253, p=.025). After stratifying girls into two groups based on use versus nonuse of hormonal contraception, plasma 3HC-cotinine ratios in girls using hormonal contraception (0.47) were substantially higher ( p<.0001) than in boys (0.25) and were significantly higher than in girls not using hormonal contraception (0.28). Controlling for cigarettes smoked per day, ethnicity, and age did not modify these results. Although plasma nicotine, cotinine, or 3HC concentrations were significantly lower in less dependent adolescent smokers, nicotine and cotinine metabolite ratios were similar. This study showed that hormonal contraception in adolescent girls may accelerate cotinine metabolism, an effect likely related to induction of cytochrome P450 2A6 and independent of ethnicity and cigarette consumption. Prospective controlled studies are needed to further evaluate the role of hormonal contraception in patterns of adolescent smoking and nicotine metabolism.

Bigos KL; Pollock BG; Coley KC; Miller DD; Marder SR; Aravagiri M et al. Sex, race, and smoking impact olanzapine exposure. Journal of Clinical Pharmacology 48(2): 157-165, 2008. (37 refs.)

Response to antipsychotics is highly variable, which may be due in part to differences in drug exposure. The goal of this study was to evaluate the magnitude and variability of concentration exposure of olanzapine. Patients with Alzheimer's disease (n =117) and schizophrenia (n = 406) were treated with olanzapine as part of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Combined, these patients (n = 523) provided 1527 plasma samples for determination of olanzopine concentrations. Nonlinear mixed-effects modeling was used to determine the population pharmacokinetics of olanzapine, and patient-specific covariates were evaluated as potential contributors to variability in drug exposure. The population mean olanzapine clearance and volume of distribution were 16.1 L/h and 2150 L, respectively. Elimination of olanzapine varied nearly 10-fold (range, 6.66-67.96 L/h). Smoking status, sex, and race accounted for 26%, 12 %, and 7% of the variability, respectively (P <. 0001). Smokers cleared olanzapine 55% faster than non/past smokers (P <. 0001). Men cleared olanzopine 38% faster than women (P <. 0001). Patients who identified themselves as black or African American cleared olanzapine 26% faster than other races (P <. 0001). Differences in olanzapine exposure due to sex, race, and smoking may account for some of the variability in response to olanzapine.

Bozikas VP; Niopas I; Kafantari A; Kanaze FI; Gabrieli C; Melissidis P et al. No increased levels of the nicotine metabolite cotinine in smokers with schizophrenia. (review). Progress in Neuro-Psychopharmacology & Biological Psychiatry 29(1): 1-6, 2005. (47 refs.)

The prevalence of smoking cigarettes has repeatedly been found to be greater in schizophrenia as compared with other psychiatric patients and the general population. Patients with schizophrenia have been found to engage in heavy smoking and consumption of higher doses of nicotine, probably by deeper inhalation of cigarettes. The aim of the current study was to assess nicotine exposure through smoking by measuring urinary cotinine, the major nicotine metabolite, in a group of smokers from Greece of smokers with schizophrenia and smokers from the general population. Participants were current smokers and belonged to one of two groups: 35 patients with schizophrenia and 48 healthy controls matched in age, education, and gender. The quantitative analysis of cotinine. the major metabolite of nicotine. in urine samples was performed by a modified high performance liquid chromatography (HPLC). Patients with schizophrenia who smoke presented a significantly larger time interval between last cigarette smoked and urine sample collection, as well as a significantly higher average number of cigarettes consumed daily than normal smokers. Urinary cotinine levels of patients with schizophrenia who smoke did not significantly differ from that of normal smokers when adjusted for average number of cigarettes per day and time interval between last cigarette smoked and urine collection. These results suggest that patients with schizophrenia did not present higher nicotine exposure through smoking compared with smokers from the community. The pharmacokinetic or pharmacodynamic properties of nicotine, as well as patient medications of the patients may explain our findings.

Bracken MB. Cotinine and spontaneous abortion: Might variations in metabolism play a role? (editorial). Epidemiology 17(5): 492-494, 2006. (15 refs.)

Britt GC; McCance-Katz EF. A brief overview of the clinical pharmacology of "club drugs". Substance Use & Misuse 40(9-10): 1189-1201, 2005. (56 refs.)

Four different "club drugs" are reviewed: MDMA (methylenedioxymethamphetamine, "Ecstasy"), GHB (gamma-hydroxybutyrate), ketamine, and Rohypnol (R) (flunitrazepam). The neurobiology, clinical pharmacology, and treatment issues for each are discussed.

Callaway JC. Fast and slow metabolizers of Hoasca. Journal of Psychoactive Drugs 37(2): 157-161, 2005. (27 refs.)

Harmine, a major alkaloid in ayahuasca (hoasca), is a selective and reversible inhibitor of the enzyme monoamine oxidase-A (MAO-A). It is also a selective inhibitor of the human cytochrome P450 isozyme 2D6 (CYP 2D6), which metabolizes harmine to a more hydrophilic derivative for eventual excretion. CYP 2D6 exhibits a wide range of polymorphisms in human populations, and variations in this enzymatic activity could account for differences in effects between individuals who use hoasca. This report broadly describes two subgroups of CYP 2D6 phenotypes-i.e., fast and slow metabolizers of harmine-in 14 experienced male members of the Uniao do Vegetal (UDV) who received a standardized dosage of hoasca. To compensate for metabolic variations in their normal religious practice, the administered dose of hoasca is always determined by the presiding mestre, who is responsible for deciding the actual amount for each individual. This age-old method compensates for metabolic variations between individuals and variations in both the alkaloid profile and strength of the hoasca.

Casale JF. Cocaethylene as a component in illicit cocaine. (letter). Journal of Analytic Toxicology 31(3): 170-171, 2007. (3 refs.)

Chahine R; Abchee A; Zalloua P. Nicotine metabolism in healthy smokers and patients with cardiovascular diseases. Molecular and Cellular Biochemistry 280(1-2): 241-244, 2005. (20 refs.)

In this study, we measured the excretion rate of nicotine and its two major metabolites, cotinine and trans-3'-hydroxycotinine (THOC), in the urine of 25 healthy smokers and 15 smokers who underwent a coronary artery bypass surgery or coronary angioplasty. After 1 day of smoking cessation, urine samples were collected in the morning, before smoking two cigarettes, and then three times after smoking, approximately 4 h apart. The results show that (i) in healthy smokers, nicotine and its two major metabolites were present at high concentration in the first urine sample after smoking, (ii) in smokers with cardiovascular disease nicotine and cotinine were less excreted whereas THOC was more excreted, mainly in the second urine sample. We conclude that this shift in nicotine metabolism may contribute to smoking-induced cardiovascular disease.

Cheatham CC; Caine-Bish N; Blegen M; Potkanowicz ES; Kamimori GH; Marcinkiewicz JL et al. The effects of nicotine on the metabolic and hormonal responses during acute cold exposure. Wilderness and Environmental Medicine 17(3): 147-157, 2006. (53 refs.)

Objective.-To examine the effects of nicotine on the metabolic and hormonal responses during acute cold exposure. Methods.-Participants in this study included 6 men and 5 women between the ages of 19 and 25 years. Each subject performed 2 cold-air trials (CATs) consisting of a 30-minute baseline (BASE) period and a 120-minute exposure to 10 degrees C air. One CAT was performed after a nicotine (NIC) dosing using a 21-mg transdermal patch, whereas the other CAT was performed after a placebo (PL) treatment. Blood samples for metabolic and hormonal measurements were obtained at the end of BASE and immediately after the cold exposure. Results.-When examining the sexes separately, there was no difference in norepinephrine between PL and NIC (P = .066). There was also no difference in epinephrine between PL and NIC in either sex (P = .634). From BASE to 120 minutes of the CAT, there was a significant decrease in cortisol (P = .036), but this response was similar between the 2 treatments (P = .077). Glucose and glycerol concentrations were not different between the PL and NIC treatments. At BASE, nonesterified fatty acid (NEFA) concentration was lower during PL compared with NIC (P = .021); however, at 120 minutes of the CAT, NEFA was greater during PL compared with NIC (P = .035). Conclusions.-During 120 minutes of cold exposure, NIC resulted in alterations in the responses in NEFA, whereas the other blood measurements were not significantly different between the 2 groups.

Crettol S; Deglon JJ; Besson J; Croquette-Krokkar M; Gothuey I; Hammig R et al. Methadone enantiomer plasma levels, CYP2B6, CYP2C19, and CYP2C9 genotypes, and response to treatment. Clinical Pharmacology & Therapeutics 78(6): 593-604, 2005. (46 refs.)

Background and Objective: Recent in vitro studies have suggested an important role of cytochrome P450 (CYP) 2B6 and CYP2C19 in methadone metabolism. We aimed to determine the influence of CYP2B6, CYP2C9, and CYP2C19 genetic polymorphism on methadone pharmacokinetics and on the response to treatment. Methods. We included 209 patients in methadone maintenance treatment on the basis of their response to treatment and their daily methadone dose. Patients were genotyped for CYP2B6, CYP2C9, and CYP2C19. Steady-state trough and peak (R)-, (S)-, and (RS)-plasma levels and peak-to-trough plasma level ratios were measured. Results: CYP2B6 genotype influences (S)-methadone and, to a lesser extent, (R)-methadone plasma levels, with the median trough (S)-methadone plasma levels being 105, 122, and 209 ng, kg/mL mg for the noncarriers of allele *6, heterozygous carriers, and homozygous carriers (*6/*6), respectively (P = .0004). CYP2C9 and CYP2C19 genotypes do not influence methadone plasma levels. Lower peak and trough plasma levels of methadone and higher peak-to-trough ratios were measured in patients considered as nonresponders [median (R,S)-methadone trough plasma levels of 183 and 249 ng (.) kg/mL (.) mg (P = .0004) and median peak-to-trough ratios of 1.82 and 1.58 for high-dose nonresponders and high-dose responders, respectively (P = .0003)]. Conclusion: Although CYP2B6 influences (S)-methadone plasma levels, given that only (R)-methadone contributes to the opioid effect of this drug, a major influence of CYP2B6 genotype on response to treatment is unlikely and has not been shown in this study. Lower plasma levels of methadone in nonresponders, suggesting a higher clearance, and higher peak-to-trough ratios, suggesting a shorter elimination half-life, are in agreement with the usual clinical measures taken for such patients, which are to increase methadone dosages and to split the daily dose into several intakes.

Cysneiros RM; Farkas D; Harmatz JS; von Moltke LL; Greenblatt DJ. Pharmacokinetic and pharmacodynamic interactions between zolpidem and caffeine. Clinical Pharmacology & Therapeutics 82(1): 54-62, 2007. (59 refs.)

The kinetic and dynamic interaction of caffeine and zolpidem was evaluated in a double-blind, single-dose, six-way crossover study of 7.5 mg zolpidem (Z) or placebo (P) combined with low-dose caffeine (250 mg), high-dose caffeine (500 mg), or placebo. Caffeine coadministration modestly increased maximum plasma concentration (C-max) and area under the plasma concentration-time curve of zolpidem by 30-40%, whereas zolpidem did not significantly affect the pharmacokinetics of caffeine or its metabolites. Compared to P + P, Z + P significantly increased sedation, impaired digit-symbol substitution test performance, slowed tapping speed and reaction time, increased EEG relative beta amplitude, and impaired delayed recall. Caffeine partially, but not completely, reversed most pharmacodynamic effects of zolpidem. Thus, caffeine only incompletely reverses zolpidem's sedative and performance-impairing effects, and cannot be considered as an antidote to benzodiazepine agonists.

De Fazio S; Gallelli L; De Siena A; De Sarro G; Scordo MG. Role of CYP3AS in abnormal clearance of methadone. Annals of Pharmacotherapy 42(6): 893-897, 2008. (43 refs.)

OBJECTIVE: To report a case of unusually low concentrations of methadone in a polydrug abuser during maintenance treatment with methadone. CASE SUMMARY: A 25-year-old man (weight 55 kg, height 165 cm) with a 12-year history of polydrug abuse was admitted to an opiates withdrawal methadone program. At the time of our observation, he was using both cannabinoids and heroin; no other medical conditions were discovered. Within the opiates withdrawal methadone program, under medical supervision, the patient started methadone therapy (20 mg/day). Two weeks later, an Abuscreen assay for methadone screening in the urine was negative and, to prevent the development of withdrawal symptoms, the dose of methadone was increased to 60 mg/day. One day later, the patient was asked to collect another urine sample in the presence of a nurse. The Abuscreen for methadone in urine remained negative. Evaluation of urinary samples collected over 24 hours documented low concentrations of methadone and high levels of 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (the primary metabolite of methadone). Evaluation for the presence of the most common polymorphisms in the cytochrome P450 and P-glycoprotein genes showed that the patient was heterozygous for the CYP3A5*1 allele and for 2 single nucleotide polymorphisms in the P-glyooprotein gene (1236C/T and 3435C/T). DISCUSSION: In this patient, poor methadone adherence was ruled out because of the presence of physicians and nurses during both methadone maintenance treatment and Abuscreen screening. Moreover, because the patient reported only heroin and cannabis at the time of evaluation, drug interactions were ruled out as possible causes for the rapid clearance of methadone. CONCLUSIONS: In this case, CYP3A5 polymorphism may have played a role in the rapid methadone metabolism.

de los Cobos JP; Sinol N; Trujols J; del Rio E; Banuls E; Luquero E et al. Association of CYP2D6 ultrarapid metabolizer genotype with deficient patient satisfaction regarding methadone maintenance treatment. Drug and Alcohol Dependence 89(2/3): 190-194, 2007. (27 refs.)

Objective: The activity of cytochrome P-450 enzyme 2D6 (CYP2D6) could be related to heroin-dependent patient satisfaction with methadone maintenance treatment. We sought to compare satisfaction with the usual methadone treatment in patients who are ultrarapid, extensive or poor metabolizers, according to CYP2D6 genotyping. Methods: Two hundred and five heroin-dependent patients filled out the Verona Service Satisfaction Scale for methadone maintenance treatment (VSSS-MT), before CYP2D6 genotyping. Results: VSSS-MT overall scores were comparable in the poor metabolizer (N = 9) and extensive metabolizer (N = 185) groups, although they were higher in poor metabolizers and extensive metabolizers taken together than in the ultrarapid metabolizers (N = 11) (p < 0.003). Likewise, ultrarapid metabolizers scored higher than the rest of the sample on the VSSS-MT Basic Interventions subscale (p < 00 1). Regarding this subscale, no poor metabolizers felt dissatisfied, and ultrarapid metabolizer males (N = 7) reported lower satisfaction than ultrarapid metabolizer females (N = 4) (p < 0.022). Ultrarapid metabolizer genotype accounted for 4.2% of the variance on the VSSS-MT total scores, and 5.0% on the Basic Intervention scores. Conclusion: Heroin-dependent patients who are CYP2D6 ultrarapid metabolizers according to genotyping present deficient satisfaction with methadone maintenance treatment.

Derby KS; Cuthrell K; Caberto C; Carmella SG; Franke AA; Hecht SS. Nicotine metabolism in three ethnic/racial groups with different risks of lung cancer. Cancer Epidemiology, Biomarkers & Prevention 17(12): 3526-3535, 2008. (48 refs.)

Previously, we documented that smoking-associated lung cancer risk is greater in Hawaiians and lower in Japanese compared with Whites. Nicotine metabolism by cytochrome P450 2A6 (CYP2A6) varies across ethnicity/race and is hypothesized to affect smoking behavior. We investigated whether higher CYP2A6 activity results in the smoker extracting more nicotine (adjusting for cigarettes per day) and being exposed to higher levels of tobacco-specific nitrosamine [4(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)] and pyrene, a representative polycyclic aromatic hydrocarbon. We conducted a cross-sectional study of 585 smokers among the three main ethnic/racial groups in Hawaii and examined whether differences in CYP2A6 activity correlate with the ethnic/racial differences in lung cancer risk. We assessed CYP2A6 activity by nicotine metabolite ratio (total traps-3-hydroxycotinine/total cotinine) and caffeine metabolite ratio (1,7-dimethyl uric acid/1,7-dimethylxanthine) in 12 h urine. We also measured urinary nicotine equivalents (sum of nicotine, cotinine, and trans-3-hydroxycotinine and their respective glucuronides), a marker of nicotine dose, 4-(methylnitrosamino)-1(3-pyridyl)-1-butanol and its glucuronide, markers of NNK exposure, and 1-hydroxypyrene, a marker of pyrene exposure. The nicotine metabolite ratio was higher in Whites than in Japanese and intermediate in Hawaiians (P values < 0.05). Cigarettes per day-adjusted nicotine equivalents were lower in Japanese compared with Hawaiians or Whites (P = 0.005 and P < 0.0001, respectively) and greater in men than women (P < 0.0001). Nicotine equivalents and total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol increased with CYP2A6 activity, indicating that smokers with greater nicotine metabolism smoke more extensively and have a higher internal NNK dose. The particularly low nicotine metabolism of Japanese smokers may contribute to their previously described decreased lung cancer risk.

Djezzar S; Dugarin J; Dally S. Zolpidem and dextromoramide abuse with increased metabolism. American Journal on Addictions 15(5): 405-406, 2006. (7 refs.)

The article studies the comparative hypnotic drug dependence between dextromoramide and methadone. Dextromoramide and zolpidem dependant patient was given either of the drugs for every two hours on consecutive days. Benzodiazepines could not replace the zolpidem effects. The patient developed withdrawal syndrome for zolpidem. Lack of zolpidem effects is due to loss of selectivity of the drug on GABA receptors. Zolpedem and methadone are metabolized by cytochrome P450 3A4 isoform. The zolepedem and dextromoramide are not known to amplify cytochrome P450 activity. An increased metabolism from genetic origin may be theorized but cannot be tested, as the basis of the interindividual variation in cytochrome P450 3A4 metabolic function is not explained fully.

Dostalek M; Jurica J; Pistovcakova J; Hanesova M; Tomandl J; Linhart I et al. Effect of methamphetamine on cytochrome P450 activity. Xenobiotica 37(12): 1355-1366, 2007. (48 refs.)

Amphetamine-based drugs, including methamphetamine, are some of the most widely used illegal drugs in the world. Methamphetamine is metabolized by the cytochrome P450s, the latter also being involved in the metabolism of many drugs and other xenobiotics. The effect of methamphetamine pretreatment (10 mg kg(-1), intraperitoneally once daily for 6 days) on the activity of the P450 enzymes was assessed both in the rat isolated perfused liver and in vivo. The rate of 4-hydroxydiclofenac production was significantly enhanced in vivo, indicating a possible stimulatory effect on P4502C6. Similarly, the kinetics of tolbutamide and dextromethorphan in isolated perfused rat liver indicate a significant increase in both P4502C6 and the P4502D subfamily. No significant changes in midazolam kinetic in the isolated perfused rat liver were observed. The potential for methamphetamine to cause drug interactions is of clinical relevance and, therefore, it warrants further investigation. Until further drug interaction experiments are accomplished, the co-administration of drugs with methamphetamine should be conducted with caution.

Dupont RL; Dupont CM. Sedatives/hypnotics and benzodiazepines. IN: Frances RJ; Miller SI; Mack AH, eds. Clinical Textbook of Addictive Disorders, 3rd edition. New York: Guilford Press, 2005. pp. 219-242. (56 refs.)

The sedatives and hypnotics, especially the benzodiazepines are widely used in medical practice. The chapter begins with efforts to distinguish between medical and nonmedical use of the benzodiazepines, and drug dependence versus physical dependence. This is followed by discussion of the pharmacology of these agents, their speed of action, metabolic pathways, reinforcement, withdrawal, and tolerance. The newer sedatives and hypnotic agents are also described.

Epstein RS. What's needed for personalized therapy in smoking cessation, (editorial). Clinical Pharmacology & Therapeutics 84(3): 309-310, 2008. (7 refs.)

it has long been known that smoking cessation is one of the most cost-effective public health opportunities available. The fact that some 22% of americans smoke, 1 despite overwhelming evidence of the consequences, reflects in part the addictive aspects of smoking and the generally modest effectiveness of various strategies for quitting. Although one of the US Department of Health and Human Services goals for the year 2010 is universal coverage of smoking-cessation agents, only about a third of payers currently cover the cost of such agents. A major disincentive is that the return on investment has been modeled to take at least 5 years to reach the break-even point, given the cost of the individual agents, the high recidivism rates, the timeline for influencing outcomes, and the relative ineffectiveness of studied agents in broad or untargeted populations. The article by Patterson et al. in this issue intriguingly suggests that there might be a way to use smokers' phenotypes to determine before treatment initiation which smokers will respond to which therapy. This approach could greatly improve the overall effectiveness of smoking-cessation agents and generate cost savings that might in turn have the effect of influencing more payers to cover these agents.

Fallon JH; Keator DB; Mbogori J; Taylor D; Potkin SG. Gender: a major determinant of brain response to nicotine. International Journal of Neuropsychopharmacology 8(1): 17-26, 2005. (29 refs.)

Biological factors responsible for nicotine initiation and dependence are largely unknown. Men and women smoke differently, and may smoke for different reasons. Brain metabolic response to nicotine may explain gender differences in nicotine use. We used FDG-PET to measure brain metabolic response on placebo and following nicotine administered by patch in 42 females and 77 males (smokers and nonsmokers) while performing a Continuous Performance Task (CPT) or the Bushman Competition and Retaliation Task (CRT). Nicotine administration affected brain metabolism much differently in males and females, and these differences were dependent on task and smoking history. In the placebo condition female smokers performing the CPT and female non-smokers performing the CRT consistently had higher brain metabolism than males, especially in the entire prefrontal system and the mid and anterior temporal lobe, language cortices, and related subcortical systems. The overall effect of nicotine was to decrease these gender differences in brain metabolism.

Feng B; Obach RS; Burstein AH; Clark DJ; de Morais SM; Faessel HM. Effect of human renal cationic transporter inhibition on the pharmacokinetics of varenicline, a new therapy for smoking cessation: An in vitro-in vivo study. Clinical Pharmacology and Therapeutics 83(4): 567-576, 2008. (45 refs.)

Varenicline is predominantly eliminated unchanged in urine, and active tubular secretion partially contributes to its renal elimination. Transporter inhibition assays using human embryonic kidney 293 cells transfected with human renal transporters demonstrated that high concentrations of varenicline inhibited substrate uptake by hOCT2 (IC50 = 890 mu M), with very weak or no measurable interactions with the other transporters hOAT1, hOAT3, hOCTN1, and hOCTN2. Varenicline was characterized as a moderate-affinity substrate for hOCT2 (Km 370 mM) and its hOCT2-mediated uptake was partially inhibited by cimetidine. Co-administration of cimetidine (1,200mg/day) reduced the renal clearance of varenicline in 12 smokers, resulting in a 29.0% (90% CI: 21.5%-36.9%) increase in systemic exposure. This increase is not considered clinically relevant, as it should not give rise to safety concerns. Consequently, it can be reasonably expected that other inhibitors of hOCT2 would not cause greater renal interactions with varenicline than that seen with the efficient hOCT2 inhibitor cimetidine.

Feng SX; Kapur S; Sarkar M; Muhammad R; Mendes P; Newland K; Roethig HJ. Respiratory retention of nicotine and urinary excretion of nicotine and its five major metabolites in adult male smokers. Toxicology Letters 173(2): 101-106, 2007. (20 refs.)

Urinary excretion of nicotine and its five major metabolites (nicotine-N-glueuronide, cotinine, cotinine-N-glueuronide, trans3'-hydroxycotinine, and trans-3'-hydroxycotinine-O-glucuronide), expressed as nicotine equivalents (NE), has been used as a biomarker of smoking-related nicotine exposure. In this open-label, single center study, we investigated the relationship between nicotine retention from smoking and urinary excretion of NE in adult smokers. After a 4-day washout period, 16 adult male smokers smoked 6 cigarettes per day for four consecutive days according to three predefined smoking patterns: no inhalation (Pattern A), normal inhalation (Pattern 13), and deep inhalation (Pattern Q. The amount of nicotine retained in the respiratory tract during smoking was estimated from the difference between the amounts of nicotine delivered and exhaled. The daily excretion of urinary NE was measured in 24 h urine samples by LC-MS/MS. The mean (+/-S.D.) amount of nicotine retained was 0.126 +/- 0.167, 0.960 +/- 0.214, and 1.070 +/- 0.223 mg/cig for Patterns A, B, and C, respectively. The mean (+/- S.D.) relative retention (the amount retained relative to the amount delivered) was 11.2 +/- 14.7%, 98.0 +/- 1.6%, and 99.6 +/- 0.3% for Patterns A, B, and C, respectively. On the fourth day of smoking, an average of 86 +/- 20% of the total daily amount of retained nicotine was recovered as NE in 24 h urine. Nicotine equivalents was treated as a single component and the data was described by a first-order elimination pharmacokinetic model which assumed instantaneous input and distribution. Based on this model, the elimination half-life of NE was 19.4 +/- 2.6 h, and the NE excretion had reached similar to 96% of the steady state levels by Day 4. Our results suggest that most of the nicotine inhaled from a cigarette is retained (>= 98%) in the lung, and at steady state, daily urine NE excretion reflects similar to 90% of the retained nicotine dose from cigarette smoking.

Fucci N; De Giovanni N. Methadone in hair and sweat from patients in long-term maintenance therapy. Therapeutic Drug Monitoring 29(4): 452-454, 2007. (11 refs.)

The authors refer to their experience with alternative matrices to supervise the methadone therapy of heroin abusers. For this purpose, hair, sweat, and urine samples were collected from 10 heroin addicts and from a control group and were submitted to gas chromatographic/mass spectroscopic analysis for methadone and its main metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), determination. The advantages of alternative matrices to urine samples in the supervision of methadone maintenance therapy are discussed. In particular, the detection of methadone in sweat could be a preferable option to the urine matrix as a result of the feasibility of sampling that allows noninvasive collection, which is not susceptible to adulteration. The ratio between EDDP and methadone in sweat and hair was also calculated to provide information about program agreement.

Gallego AO; Baron MG; Arranz EE. Oxycodone: a pharmacological and clinical review. (review). Clinical & Translational Oncology 9(5): 298-307, 2007. (72 refs.)

Oxycodone is a semi-synthetic opioid with an agonist activity on mu, kappa and delta receptors. Equivalence with regard to morphine is 1:2. Its effect commences one hour after administration and lasts for 12 h in the controlled-release formulation. Plasma half-life is 3-5 h (half that of morphine) and stable plasma levels are reached within 24 h (2-7 days for morphine). Oral bioavailability ranges from 60 to 87%, and plasma protein binding is 45%. Most of the drug is metabolised in the liver, while the rest is excreted by the kidney along with its metabolites. The two main metabolites are oxymorphone - which is also a very potent analgesic and noroxycodone, a weak analgesic. Oxycodone metabolism is more predictable than that of morphine, and therefore titration is easier. Oxycodone has the same mechanism of action as other opioids: binding to a receptor, inhibition of adenylyl-cyclase and hyperpolarisation of neurons, and decreased excitability. These mechanisms also play a part in the onset of dependence and tolerance. The clinical efficacy of oxycodone is similar to that of morphine, with a ratio of 1/1.5-2 for the treatment of cancer pain. Long-term administration may be associated with less toxicity in comparison with morphine. In the future, both opioids could be used simultaneously at low doses to reduce toxicity. It does not appear that there are any differences between immediate and slow-release oxycodone, except their half-life is 3-4 h, and 12 h, respectively. In Spain, controlled-release oxycodone (OxyContin (R)) is marketed as 10-, 20-, 40- or 80-mg tablets for b.i.d. administration. Tablets must be taken whole and must not be broken, chewed or crushed. There is no food interference. The initial dose is 10 mg b.i.d. for new treatments and no dose reduction is needed in the elderly or in cases of moderate hepatic or renal failure. Immediate-release oxycodone (OxyNorm (R)) is also available in capsules and oral solution. Side effects are those common to opioids: mainly nausea, constipation and drowsiness. Vomiting, pruritus and dizziness are less common. The intensity of these side effects tends to decrease over the course of time. Oxycodone causes somewhat less nausea, hallucinations and pruritus than morphine.

Glaz-Sandberg A; Dietz L; Nguyen H; Oberwittler H; Aderjan R; Mikus G. Pharmacokinetics of 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol (CTHC) after intravenous administration of CTHC in healthy human subjects. Clinical Pharmacology & Therapeutics 82(1): 63-69, 2007. (37 refs.)

After cannabis consumption there is only limited knowledge about the pharmacokinetic (PK) and metabolic properties of 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol (CTHC), which is formed by oxidative breakdown from Delta(9)-tetrahydrocannabinol (THC). Despite widely-varying concentrations observed in smoking studies, attempts have been made to interpret consumption behavior with special regard to a cumulated or decreasing concentration of CTHC in serum. Ten healthy nonsmoking white male individuals received 5 mg CTHC intravenously over 10 min. Highest serum concentrations of CTHC were observed at the end of the infusion (336.8 +/- 61.7 mu g/l) followed by a quick decline. CTHC concentration could be quantified up to 96 h after administration, with a terminal elimination half-life of 17.6 +/- 5.5 h. Total clearance was low (91.2 +/- 24.0 ml/min), with renal clearance having only a minor contribution (0.136 +/- 0.094 ml/min). This first metabolite-based kinetic approach will allow an advanced understanding of CTHC PKs data obtained in previous studies with THC.

Grassi MC; Cioce AM; Giudici FD; Antonilli L; Nencini P. Short-term efficacy of Disulfiram or Naltrexone in reducing positive urinalysis for both cocaine and cocaethylene in cocaine abusers: A pilot study. Pharmacological Research 55(2): 117-121, 2007. (38 refs.)

Cocaine abusers frequently report taking the drug in association with alcohol. This combined intake leads to the synthesis of cocaethylene, an active metabolite with effects similar to those of cocaine, but more prolonged. Since pharmacological effects of cocaethylene may partially account for the habit of cocaine abusers to take the drug in combination with ethanol, a main therapeutic goal in these patients should be making body fluids negative for cocaethylene. This randomized controlled open study conducted on 12 subjects co-abusers of cocaine and alcohol, evaluates the efficacy of a 12-week pharmacological treatment with Disulfiram (DIS) 400 mg daily or Naltrexone (NTX) 50 mg daily associated with Cognitive Behaviour Therapy (CBT), as compared to CBT alone, in terms of: (i) stay in treatment; (ii) drug-free urinalyses for cocaine and cocaethylene; (iii) reduction of alcohol and cocaine craving. Data presented in this study are restricted to the first 4 weeks of treatment when all the enrolled subjects were still available for examination. In fact, of the 12 subjects enrolled in the study only 4 (33%) completed the 12-week treatment. Of these, three were in the CBT group and one in the NTX/CBT group. Results show that CBT treated subjects remained in treatment longer than those assigned to either DIS/CBT or NTX/CBT therapies. However, during the first 4 weeks of treatment, CBT-group urine tested positive almost always for both cocaine and cocaethylene. In contrast, both DIS/CBT and NTX/CBT treatments were associated to a statistically significant reduction, of positive urinalysis for both cocaine and cocaethylene, with respect to CBT alone. Moreover, across the first 4 weeks of treatment DIS/CBT and NTX/CBT treated subjects maintained lower scores at Visual Analogue Scales (VAS) for both cocaine and alcohol craving than subjects receiving CBT alone. This pilot study suggests that the transient efficacy of pharmacological treatments in maintaining subjects drug free, does not add to the capability of CBT to retain them in treatment.

Greenblatt DJ; von Moltke LL. Gender has a small but statistically significant effect on clearance of CYP3A substrate drugs. Journal of Clinical Pharmacology 48(11): 1350-1355, 2008. (42 refs.)

The role of gender on the disposition of drugs metabolized by cytochrome P4503A (CYP3A) remains controversial. Some sources suggest that CYP3A activity in women exceeds that in men, but evidence to support this position is inconsistent at best. We evaluated 38 data sets in which clearance of CYP3A substrate drugs was studied in healthy young male and young female subjects. None of these drugs was a substrate for transport by P-glycoprotein (P-gp). The overall mean ( SE) for the female/male ratio of weight-normalized clearance was 1.26 (+/- 0.07) for parenteral dosage and 1.17 (+/- 0.07) for oral dosage. Both ratios were significantly different (P <.05) from 1.0. For oral dosage studies, the female/male clearance ratio was unrelated to the drug's absolute oral bioavailability Thus gender has a small and statistically significant, although most likely clinically unimportant, influence on CYP3A phenotype for substrates not transported by P-gp.

Hieronymus TL; Nanovskaya TN; Deshmukh SV; Vargas R; Hankins GDV; Ahmed MS. Methadone metabolism by early gestational age placentas. American Journal of Perinatology 23(5): 287-294, 2006. (32 refs.)

The objective of this study was to identify the enzyme that metabolizes methadone in preterm placentas. Microsomal fractions were obtained from preterm (17 to 34 weeks) placentas (36 total; 12 per each gestational age group) and their activity in metabolizing methadone to 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) was determined. The enzyme catalyzing the reaction was identified by using chemical inhibitors selective for various cytochrome P450 isozymes and monoclonal antibodies raised against them. The metabolism of methadone by microsomes revealed saturation kinetics. Methadone was N-demethylated to EDDP by aromatase. The affinity of methadone to aromatase (apparent K-m) did not change with gestation, but the activity of the enzyme (V-max) increased and varied widely between individual placentas. Aromatase/CY-P19 is the placental enzyme metabolizing methadone during pregnancy. The variability in enzyme activity among individuals should be reflected by the concentration of methadone in the fetal circulation and might be one of the factors affecting the incidence and intensity of neonatal abstinence syndrome.

Hooker JM; Xu YW; Schiffer W; Shea C; Carter P; Fowler JS. Pharmacokinetics of the potent hallucinogen, salvinorin A in primates parallels the rapid onset and short duration of effects in humans. Neuroimage 41(3): 1044-1050, 2008. (27 refs.)

Salvia divinorum, a mint plant originally used by the Mazatecs of Oaxaca, Mexico in spiritual rituals has gained popularity, in smoked form, as a legal hallucinogen in the United States and Europe. Abuse results in rapid onset and short-lasting effects that include visual hallucinations and motor-function impairment. Salvinorin A, the psychoactive component of S. divinorum, is a uniquely potent agonist at kappa-opioid receptors, targets for new therapeutic drugs. We labeled salvinorin A with C-11 by acylation of salvinorin B with [C-11]-acetyl chloride to study whether its kinetic behavior in the brain parallels its uniquely fast, yet brief physiological effects. Positron emission tomography (PET) studies performed in 6 adult female baboons indicated extremely rapid brain uptake reaching a peak accounting for 3.3% of the total administered dose in 40 s and clearing with a half-life of 8 min. [C-11]-salvinorin A was distributed throughout the brain with the highest concentration in the cerebellum and a notable concentration in the visual cortex, perhaps accounting for its physiological effects when smoked. Naloxone administration did not reduce the overall concentration of [C-11]-salvinorin A significantly nor did it change its regional distribution. Peripheral organ kinetics suggested at least two modes of metabolism and excretion occur: through the renal and biliary systems. Our findings have revealed that the exceptionally rapid uptake and brief duration of salvinorin A in the brain match the time-course of visual hallucinations for S. divinorum when smoked. The effects of salvinorin A may occur at <10 mu g in the human brain, emphasizing its remarkable potency.

Huang SW; Cook DG; Hinks LJ; Chen XH; Ye S; Gilg JA et al. CYP2A6, MAOA, DBH, DRD4, and 5HT2A genotypes, smoking behaviour and cotinine levels in 1518 UK adolescents. Pharmacogenetics and Genomics 15(12): 839-850, 2005. (55 refs.)

Objectives: Smoking is a major cause of death and often initiates in adolescence. Mutations in CYP2A6 slow metabolism of nicotine to cotinine. Haploinsufficiency in adults is associated with lower cigarette consumption, lower cotinine level and higher quit rates. Other genes are also implicated in smoking behaviour. We explored smoking behaviour and cotinine levels in relation to genotypes in adolescents. Methods: 1518 subjects from the Ten Towns Heart Health Study were genotyped for CYP2A6 alleles *1A, *1B, *2, *4, *5, *9 and *12 to classify predicted nicotine metabolism rate. DBH(rs77905), MAOA(rs1801291 +VNTR), DRD4(VNTR) and 5HT2A(rs6313) were also studied. Smoking status was established by questionnaire and salivary cotinine measurement at 13-15 and 18 years. Results: No significant associations were identified for DBH, MAOA, DRD4 and 5HT2A markers, with smoking status or cotinine level at either age. At age 18, haploin-sufficiency (HI) for CYP2A6 was associated with a higher odds of being a current smoker compared with the *1B carriers (WT1B) (OR = 2.23 (1.16, 4.27) for current versus ex); *1A homozygotes (WT1A) were also at slightly higher risk (OR= 1.44 (1.01, 2.06)). Partial haploinsufficiency (PHI) was not associated with being a current smoker. There were no significant associations at age 13-15. PHI and HI were associated with higher cotinine levels amongst smokers at both 13-15 and at 18 years compared with WT1B and WT1A groups. Conclusions: CYP2A6 haploinsufficiency increases likelihood of continuing smoking in teenagers. We hypothesize an explanatory 'occupancy' model to explain why haploinsufficiency results in faster progression to nicotine dependence, but lower subsequent consumption.

Huestis MA. Human cannabinoid pharmacokinetics. (review). Chemistry & Biodiversity 4(8): 1770-1804, 2007. (189 refs.)

This review article deals with the pharmacokinetics of cannabinoids. There are two major sections; the first deals with absorption, distribution, metabolism and elimination. The discussion considers the effects of different routes of administration, metabolism, by both hepatic and extrahepatic routes, the terminal elimination half lives of THC-COOH, the percentage of THC excreted as urinary THC-COOH, cannabinoid -glucuronide conjugates, and urinary biomarkers of recent cannabis use. The second major section deals with the interpretation of cannabinoid concentrations in biological fluids, both plasma and urine, as well as oral fluid and sweat. Again consideration is given to the impact of route of administration, concentrations after frequent use, and detection windows.

Johnstone E; Benowitz N; Cargill A; Jacob R; Hinks L; Day I et al. Determinants of the rate of nicotine metabolism and effects on smoking behavior. Clinical Pharmacology & Therapeutics 80(4): 319-330, 2006. (39 refs.)

Background: Studies on cytochrome P450 (CYP) 2A6 suggest that genotype affects the rate of nicotine metabolism and, consequently, cigarette consumption. However, known alleles of CYP2A6 associated with fast or slow metabolism are relatively uncommon, and there remains considerable variation in metabolic activity among those with presumed wild-type CYP2A6 alleles, suggesting that other genetic or environmental factors also influence the rate of nicotine metabolism. Methods. We investigated determinants of the rate of nicotine metabolism and effects on smoking behavior in a United Kingdom cohort who participated in a placebo-controlled trial of smoking cessation via nicotine replacement therapy. Those who continued to smoke cigarettes at the 8-year follow-up formed our study group (N = 545). The ratio of the nicotine metabolite trans-3'-hydroxycotinine to cotinine in plasma was used as an index of CYP2A6 activity and thus as a marker of the rate of nicotine metabolism. Results: The nicotine metabolite ratio was associated with sex (P < .0001), CYP2A6 genotype (*1B, *2, *4, *9, and *12) (P < .0001), CYP2B6 haplotype (*4-dominant) (P =.02), plasma nicotine concentration (P < .0001), and age (P =.02) but was not associated with dependence score (P > .20). The ratio also predicted the number of cigarettes smoked at will per day, although the association was weak (F1,492 = 4.05, P =.04). Conclusion: In this cohort the rate of nicotine metabolism is related to age, sex, CYP2A6 genotype, and CYP2B6 genotype and may affect the level of tobacco consumption.

Jones AW; Holmgren A; Kugelberg FC. Concentrations of cocaine and its major metabolite benzoylecgonine in blood samples from apprehended drivers in Sweden. Forensic Science International 177(2-3): 133-139, 2008. (28 refs.)

Cocaine and its major metabolite benzoylecgonine (BZE) were determined in blood samples from people arrested in Sweden for driving under the influence of drugs (DUID) over a 5-year period (2000-2004). Venous blood or urine if available, was subjected to a broad toxicological screening analysis for cannabis, cocaine metabolite, amphetamines, opiates and the major benzodiazepines. Verification and quantitative analysis of cocaine and BZE in blood was done by gas chromatography-mass spectrometry (GC-MS) at limits of quantitation (LOQ) of 0.02 mg/L for both substances. Over the study period 26,567 blood samples were analyzed and cocaine and/or BZE were verified in 795 cases (3%). The motorists using cocaine were predominantly men (>96%) with an average age of 28.3 +/- 7.1 years ( standard deviation, S.D.). The concentration of cocaine was below LOQ in 574 cases although BZE was determined at mean, median and highest concentrations of 0.19 mg/L, 0.12 mg/L and 1.3 mg/L, respectively. In 221 cases, cocaine and BZE were together in the blood samples at mean and (median) concentrations of 0.076 mg/L (0.05 mg/L) and 0.859 mg/L (0.70 mg/L), respectively. The concentrations of BZE were always higher than the parent drug; mean BZE/cocaine ratio 14.2 (median 10.9) range 1-55. Cocaine and BZE were the only psychoactive substances reported in N = 61 cases at mean (median) and highest concentrations of 0.095 (0.07) and 0.5 mg/L for cocaine and 1.01 (0.70) and 3.1 mg/L for BZE. Typical signs of drug influence noted by the arresting police officers included bloodshot and glossy eyes, agitation, difficulty in sitting still and incoherent speech.

Jones AW; Karlsson L. Relation between blood- and urine-amphetamine concentrations in impaired drivers as influenced by urinary pH and creatinine. Human and Experimental Toxicology 24(12): 615-622, 2005. (15 refs.)

Amphetamine undergoes extensive renal excretion and significant amounts are present in urine as the unchanged parent drug. This prompted us to investigate whether a quantitative relationship existed between blood and urine concentrations of amphetamine in the body fluids of drug-impaired drivers apprehended in Sweden, where this stimulant is the major drug of abuse. The relationship between blood and urine concentrations of amphetamine was determined by multivariate analysis with urinary pH and creatinine as predictor variables. Amphetamine was determined in blood and urine by gas chromatography-mass spectrometry with deuterium-labelled internal standards. The concentration of amphetamine in urine was about 200 times greater than the concentration in blood; the mean and median urine/blood ratios were 214 and 160, respectively, with large individual variations. The Pearson correlation coefficient between urine (y) and blood (x) amphetamine was r = 0.53, n = 48, which was statistically highly significant (P < 0.001), although the residual standard deviation (SD) was large (+/- 181 mg/L). The correlation coefficient increased (r = 0.60) when the concentration of amphetamine in urine was normalized for dilution by dividing with the creatinine content. When urinary pH and creatinine were both included as predictor variables, the correlation coefficient was even higher (r = 0.69), now explaining 48% (r(2) = 0.48) of the variation in urine-amphetamine concentration. However, the partial regression coefficient for creatinine (53 +/- 28.7) was not statistically significant (t = 1.85, P > 0.05), whereas the corresponding regression coefficient for pH was highly significant and had a negative sign (-102 +/- 32.6, t = -3.12, P < 0.005). Other factors could impact on the urine-blood amphetamine relationship, such as route of administration, pattern of voiding and time elapsed after use of the drug.

Joseph AM; Hecht SS; Murphy SE; Carmella SG; Le CT; Zhang Y et al. Relationships between cigarette consumption and biomarkers of tobacco toxin exposure. Cancer Epidemiology, Biomarkers & Prevention 14(12): 2963-2968, 2005. (22 refs.)

Epidemiologic studies show a dose-response relationship between cigarettes per day and health outcomes such as heart and lung disease, and health outcomes are related to some biomarkers of tobacco exposure. The objective of this study was to examine the relationships between cigarettes per day and levels of selected biomarkers of tobacco toxin exposure: carbon monoxide (CO), metabolites of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and polycyclic aromatic hydrocarbons [total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and 1-hydroxypyrene (1-HOP), respectively], and total cotinine (cotinine plus cotinine-N-glucuronide). We did a cross-sectional analysis of merged data from (a) two clinical trials and (b) two cohorts of light smokers (total n = 400). The mean age of participants was 50.4 years and the range of cigarette consumption was 1 to 100/d; however, few subjects smoked >45 cigarettes/d (n = 12). Results show that levels of the biomarkers CO, total NNAL, and total cotinine increase with an increase in the number of cigarettes smoked per day, but not in a linear fashion. 1-HOP is a less discriminating biomarker as levels are relatively stable regardless of the number of cigarettes smoked per day. There is considerable variability in toxin measurement, especially at high levels of smoking. There was a significant correlation between cigarettes per day and total NNAL, 1-HOP, total cotinine, and CO. Total NNAL was highly significantly correlated with total cotinine and CO and also significantly correlated with 1-HOP. These findings suggest that the number of cigarettes smoked per day is not necessarily a reliable measure of toxin exposure and may underestimate tobacco toxin exposure at low levels of smoking or overestimate exposure at high levels of smoking.

Kamata HT; Shima N; Zaitsu K; Kamata T; Miki A; Nishikawa M et al. Metabolism of the recently encountered designer drug, methylone, in humans and rats. Xenobiotica 36(8): 709-723, 2006. (18 refs.)

The urinary metabolites of methylone in humans and rats were investigated by analysing urine specimens from its abuser and after administrating to rats with gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-electrospray ionization mass spectrometry (LC-ESI MS), using authentic standards. The time-course excretion profiles of methylone and its three metabolites in rats were further investigated after a single intraperitoneal dosing of 5mg kg(-1) methylone hydrochloride. Two major metabolic pathways were revealed for both humans and rats as follows: (1) side-chain degradation by N-demethylation to the corresponding primary amine methylenedioxycathinone (MDC), partly conjugated; and (2) demethylenation followed by O-methylation of either a 3- or 4-OH group on the benzene ring to produce 4-hydroxy-3-methoxymethcathinone (HMMC) or 3-hydroxy-4-methoxymethcathinone (3-OH-4-MeO-MC), respectively, mostly conjugated. Of these metabolites, HMMC was the most abundant in humans and rats. The cumulative amount of urinary HMMC excreted within the first 48 h in rats was approximately 26% of the dose, and the amount of the parent methylone was not more than 3%. These results demonstrate that the analysis of HMMC will be indispensable for proof of the use of methylone in forensic urinalysis.

Kandel DB; Schaffran C; Griesler PC; Hu MC; Davies M; Benowitz N. Salivary cotinine concentration versus self-reported cigarette smoking: Three patterns of inconsistency in adolescence. Nicotine & Tobacco Research 8(4): 525-537, 2006. (35 refs.)

The present study examined the extent and sources of discrepancies between self-reported cigarette smoking and salivary cotinine concentration among adolescents. The data are from household interviews with a cohort of 1,024 adolescents from an urban school system. Histories of tobacco use in the last 7 days and saliva samples were obtained. Logistic regressions identified correlates of three inconsistent patterns: (a) Pattern 1-self-reported nonsmoking among adolescents with cotinine concentration above the 11.4 ng/mg cutpoint (n=176), (b) Pattern 2 - low cotinine concentration (below cutpoint) among adolescents reporting having smoked within the last 3 days (n=155), and (c) Pattern 3-high cotinine concentration (above cutpoint) among adolescents reporting not having smoked within the last 3 days (n=869). Rates of inconsistency were high among smokers defined by cotinine levels or self-reports ( Pattern 1=49.1%; Pattern 2=42.0%). Controlling for other covariates, we found that reports of nonsmoking among those with high cotinine (Pattern 1) were associated with younger age, having few friends smoking, little recent exposure to smokers, and being interviewed by the same interviewer as the parent and on the same day. Low cotinine concentration among self-reported smokers (Pattern 2) was negatively associated with older age, being African American, number of cigarettes smoked, depth of inhalation, and exposure to passive smoke but positively associated with less recent smoking and depressive symptoms. High cotinine concentrations among self-reported nonsmokers was positively associated with exposure to passive smoke ( Pattern 3). The data are consonant with laboratory findings regarding ethnic differences in nicotine metabolism rate. The inverse relationship of cotinine concentration with depressive symptoms has not previously been reported. Depressed adolescent smokers may take in smaller doses of nicotine than nondepressed smokers; alternatively, depressed adolescents may metabolize nicotine more rapidly.

Kim SS; Ziedonis D; Chen KW. Tobacco use and dependence in Asian Americans: A review of the literature. (review). Nicotine & Tobacco Research 9(2): 169-184, 2007. (116 refs.)

This article reports on an integrative review of literature on Asian American tobacco use and dependence, identifies gaps in the literature, and proposes studies needed in the future. Articles were retrieved from electronic health-related databases indexed for permutations of the keywords Asian Americans, smoking, tobacco use, tobacco dependence, and nicotine dependence. A manual search also was done to identify additional literature. A total of 216 articles were identified; the review includes 39 articles reporting gender- and ethnic-specific information on subgroups of Asian Americans in the following areas: Smoking prevalence, correlates of smoking, and tobacco dependence treatment. In addition, 13 articles on tobacco and nicotine metabolism were reviewed. Empirical studies have concentrated on Chinese, Korean, and Vietnamese American men. Smoking prevalence is higher among Asian American men with low acculturation than among their counterparts, but the reverse pattern is observed among Asian American women. Asian Americans tend to smoke fewer cigarettes per day than White Americans, and this difference may be explained by differences between the two groups in nicotine metabolism. More research is needed on this diverse population, especially Asian American women of all ethnic subgroups and Asian Indian, Filipino, Pakistani, and Thai American men. A need also exists for the development of specialized tobacco dependence treatments to address the cultural issues of specific Asian American ethnic subgroups, to enhance access to treatment, and to determine how treatment recommendations should reflect differences in acculturation level and tobacco and nicotine metabolism.

Kolbrich EA; Barnes AJ; Gorelick DA; Boyd SJ; Cone EJ; Huestis MA. Major and minor metabolites of cocaine in human plasma following controlled subcutaneous cocaine administration. Journal of Analytical Toxicology 30(8): 501-510, 2006. (39 refs.)

Cocaine is rapidly metabolized to major metabolites, benzoylecgonine (BE) and ecgonine methyl ester (EME), and minor metabolites, norcocaine, p-hydroxycocaine, m-hydroxycocaine, p-hydroxybenzoylecgonine (pOHBE), and m-hydroxybenzoylecgonine. This IRB-approved study examined cocaine and metabolite plasma concentrations in 18 healthy humans who provided written informed consent to receive low (75 mg/70 kg) and high (150 mg/70 kg) subcutaneous cocaine hydrochloride doses. Plasma specimens, collected prior to and up to 48 h after dosing, were analyzed by gas chromatography-mass spectrometry (2.5 ng/mL limits of quantification). Cocaine was detected within 5 min, with mean+/-SE peak concentrations of 300.4+/-24.6 ng/mL (low) and 639.1+/-56.8 ng/mL (high) 30-40 min after dosing. BE and EME generally were first detected in plasma 5-15 min post-dose; 2-4 h after dosing, BE and EME reached mean maximum concentrations of 321.3+/-18.4 (low) and 614.7+/-46.0 ng/mL (high) and 47.4+/-3.0 (low) and 124.4+/-18.2 ng/mL (high), respectively. Times of last detection were BE>EME>cocaine. Minor metabolites were detected much less frequently for up to 32 h, with peak concentrations of 18 ng/mL for all analytes except pOHBE (up to 57.7 ng/mL). These data improve our knowledge of the pharmacokinetics of cocaine and its major and minor metabolites in plasma following controlled subcutaneous cocaine administration.

Koren G; Blanchette P; Lubetzky A; Kramer M. Hair nicotine: Cotinine metabolic ratio in pregnant women: A new method to study metabolism in late pregnancy. Therapeutic Drug Monitoring 30(2): 246-248, 2008. (14 refs.)

A large number of smoking women cannot quit their habit when they become pregnant. Preliminary evidence suggests an enhanced nicotine clearance rate in late pregnancy. To evaluate the change in nicotine metabolism in late pregnancy, we undertook a prospective cohort study of a large, diverse group of pregnant women recruited from four Montreal maternal hospitals. Smoking histories were obtained by structured questionnaires administered at 24 to 26 weeks of gestation and postpartum. Hair concentrations of nicotine and cotinine were measured by immunoassays for each trimester based on sectioning the hair and assuming average hair growth of I cm per month. A strong correlation was observed between average number of cigarettes smoked per day and hair nicotine and cotinine in all three trimesters. A significant decrease in hair nicotine was observed among steady smokers from the first to third trimester paralleled by a significant increase in hair cotinine. The ratio of hair nicotine: cotinine decreased significantly from the first to the third trimester. Increased nicotine metabolism in late pregnancy results in lower systemic exposure to nicotine. This phenomenon may explain why many pregnant women feel the urge to continue smoking and why standard-dose nicotine replacement therapy has not been effective in reducing smoking during pregnancy in several clinical trials.

Kotlyar M; Mendoza-Baumgart MI; Li ZZ; Pentel PR; Barnett BC; Feuer RM; Smith EA; Hatsukami DK. Nicotine pharmacokinetics and subjective effects of three potential reduced exposure products, moist snuff and nicotine lozenge. Tobacco Control 16(2): 138-142, 2007. (25 refs.)

Objective: To compare nicotine pharmacokinetics and subjective effects of three new smokeless tobacco potential reduced exposure products (PREPs; Ariva, Revel and Stonewall) with moist snuff (Copenhagen) and medicinal nicotine (Commit lozenge). Methods: 10 subjects completed a randomised, within-subject, crossover study. Subjects used one product for 30 min at each of the five laboratory sessions. Maximal nicotine concentration (C-max) was determined and area under the concentration time curve (AUC) was calculated for a 90-min period (during use and 60 min after use). Nicotine craving, withdrawal symptoms and ratings of product effects and liking were measured during product use. Results: Nicotine AUC and Cmax were higher for Copenhagen than for any other product (p < 0.002) and higher for Commit than for either Ariva or Revel (p < 0.001). C-max for Commit was also higher than for Stonewall (p=0.03). Craving was lowest during use of Copenhagen (p < 0.03). Craving during use of Stonewall, Ariva and Commit was lower than during use of Revel (p < 0.05). Withdrawal symptom score during use of Copenhagen was lower than during use of Revel (p=0.009). Copenhagen scores were higher (p < 0.005) than all other products in several measures of drug effects and liking (feel good effects, satisfaction, liking and desire for product, and strength of product). Conclusion: The new smokeless tobacco PREPs result in lower nicotine concentrations and equivalent or lower reductions in subjective measures compared with medicinal nicotine. Since health effects of PREPs are largely unknown, medicinal nicotine should be preferentially encouraged for smokers or smokeless tobacco users wishing to switch to lower-risk products.

Kubota T; Nakajima-Taniguchi C; Fukuda T; Funamoto M; Maeda M; Tange E et al. CYP2A6 polymorphisms are associated with nicotine dependence and influence withdrawal symptoms in smoking cessation. Pharmacogenomics Journal 6(2): 115-119, 2006. (18 refs.)

CYP2A6 is the main enzyme that catalyzes nicotine into cotinine. Interindividual differences in nicotine metabolism result at least partially from polymorphic variation of CYP2A6 gene. In this study, we evaluated the influence of CYP2A6 polymorphisms on clinical phenotypes of smoking, such as smoking habit and withdrawal symptoms. Japanese smokers (n = 107) were genotyped for CYP2A6*1, *4 and *9. Consistent with the previous reports, CYP2A6 genotypes have a tendency to correlate with the number of cigarettes per day and with daily intake of nicotine. Interestingly, CYP2A6 high-activity group (CYP2A6*1/*1, *1/*9, *1/*4, *9/*9) smoked the first cigarette of the day earlier than low-activity group (CYP2A6*4/*9, *4/*4), indicating more remarkable nicotine dependence. Furthermore, nicotine withdrawal symptoms were more serious in smoking cessation in CYP2A6 high-activity group. Collectively, CYP2A6 genotypes are related with nicotine dependence, influencing smoking habits and withdrawal symptoms in quitting smoking. It is proposed that individualized smoking cessation program could be designed based on CYP2A6 genotypes.

Lawson CC; LeMasters GK. Regarding "Caffeine metabolism, genetics, and perinatal outcomes: A review of exposure assessment considerations during pregnancy" (letter). Annals of Epidemiology 16(9): 733-733, 2006. (3 refs.)

Lee AM; Jepson C; Shields PG; Benowitz N; Lerman C; Tyndale RF. CYP2B6 genotype does not alter nicotine metabolism, plasma levels, or abstinence with nicotine replacement therapy (editorial). Cancer Epidemiology, Biomarkers & Prevention 16(6): 1312-1314, 2007. (15 refs.)

Lerman C; Tyndale R; Patterson F; Wileyto EP; Shields PG; Pinto A et al. Nicotine metabolite ratio predicts efficacy of transdermal nicotine for smoking cessation. Clinical Pharmacology & Therapeutics 79(6): 600-608, 2006. (30 refs.)

Background. Nicotine is metabolized to cotinine, and cotinine is metabolized to 3'-hydroxycotinine (3-HC) by the liver enzyme cytochrome P450 (CYP) 2A6. More rapid metabolism of nicotine may result in lower nicotine blood levels from nicotine replacement products and poorer smoking cessation outcomes. This study evaluated the utility of the 3-HC/cotinine ratio as a predictor of the efficacy of nicotine replacement therapy as an aid for smoking cessation. Methods. By use of an open-label design, 480 treatment-seeking smokers were randomly assigned to 8 weeks of transdermal nicotine or nicotine nasal spray use, plus behavioral group counseling. Assessments included demographics, smoking history, body mass index, and plasma nicotine, cotinine, and 3-HC concentrations, as well as CYP2A6 genotypes. Smoking cessation was biochemically verified at the end of treatment and at 6-month follow-up. Results: The rate of nicotine metabolism, as indicated by pretreatment 3-HC/cotinine ratio derived from cigarette smoking, predicted the effectiveness of transdermal nicotine at both time points. The odds of abstinence were reduced by almost 30% with each increasing quartile of metabolite ratio (odds ratio, 0.72 [95% confidence interval, 0.57-0.90]; P=.005). Higher metabolite. ratios also predicted lower nicotine concentrations (beta=-1.72, t(179)=-3.31, P < .001), as well as more severe cravings for cigarettes after 1 week of treatment (beta = 0.32, t(190)=2.91, P=.004). The metabolite ratio did not predict cessation with use of nicotine nasal spray (odds ratio, 1.05 [95% confidence interval, 0.83-1.33]; P=.68). Conclusion: The nicotine metabolite ratio might be useful in screening smokers to determine likely success with a standard dose of transdermal nicotine.

Levi M; Dempsey DA; Benowitz NL; Sheiner LB. Population pharmacokinetics of nicotine and its metabolites I. Model development. Journal of Pharmacokinetics and Pharmacodynamics 34(1): 5-21, 2007. (15 refs.)

We present a mechanistic population model for the pharmacokinetics of nicotine (NIC), its primary (CYP2A6-generated) metabolite cotinine (COT), and COT's primary (CYP2A6-generated) metabolite, trans-3'-hydroxycotinine (3HC). Sixty-six subjects received oral deuterium-labeled NIC (NIC-d(2), 2 mg), and COT (COT-d(4), 10mg) simultaneously. Frequent plasmalsaliva samples were taken for measurement of concentrations of NIC-d(2), COT-d(2), 3HC-d(2), COT-d(4), and 3HC-d(4). A mechanistic population pharmacokinetic model was fitted to all data simultaneously. Most of the pharmacokinetic parameters found here agree with previous studies and with a previous model-independent analysis of these data. However, 3HC t(1/2) was found to be considerably shorter than a previously reported value, possibly because 3HC elimination was saturated with the larger doses used in the previous study. Additionally, the delay in the appearance of COT-d2 in the blood was modeled as a time delay (t(1/2) = 12 min) in its release from the liver following NIC-d(2) administration. The most important result of the previous model-independent analysis of these data, confirmed here, is that NIC clearance to COT and the 3HC: COT saliva concentration ratio are highly correlated (r = 0.7-0.8). The correlation above support that idea that the 3HC: COT ratio can be used as a predictor of CYP2A6 activity and nicotine clearance. The model-based analysis extends and further justifies this conclusion.

Mabry PL; Tooze JA; Moser RP; Augustson EM; Malcolm RJ; Benowitz NL. Nicotine, cotinine, withdrawal, and craving patterns during smoking and nicotine nasal spray use: Results from a pilot study with African American men. Nicotine & Tobacco Research 9(1): 65-82, 2007. (53 refs.)

Nicotine intake via smoking is highly variable. Individualized dosing of nicotine replacement therapy (NRT) may improve product efficacy, but a better understanding of the within-day and within-subject relationships between smoking, NRT use, nicotine and cotinine concentrations in blood, and cravings and withdrawal symptoms is needed to inform dosing algorithms. A pilot study was undertaken to collect data on these relationships and to assess the feasibility of the methods needed for this type of research, including a sophisticated statistical modeling technique (a two-part mixed-effects model with correlated random effects that accounts for clumping at zero). Because nicotine metabolism varies by gender and race, the sample was homogeneous with respect to these characteristics. In a within-subjects study, 27 African American adult male smokers carried a computerized cigarette dispenser for 1 week, capturing the time each cigarette was smoked. Subjects then entered an inpatient setting for 1 day of scheduled smoking (matched to data from the cigarette dispenser to create an ecologically valid schedule) and 4 days of ad libitum nicotine nasal spray use, while tobacco abstinent. Eight times per day, at 2-hour intervals, blood was drawn and ratings of cigarette cravings and withdrawal symptoms were obtained. On average, subjects used less than half of the manufacturer's recommended minimum daily dose of nicotine nasal spray. Large differences in nicotine and cotinine levels were observed between individuals. When predicting nicotine, cotinine, withdrawal, and cravings, we observed significant interactions between route of nicotine intake and a variety of independent variables.

Mandrioli R; Mercolini L; Raggi MA. Benzodiazepine metabolism: An analytical perspective. (review). Current Drug Metabolism 9(8): 827-844, 2008. (186 refs.)

Benzodiazepines are currently among the most frequently prescribed drugs all over the world. They act as anxiolytics, sedatives, hypnotics, amnesics, antiepileptics and muscle relaxants. Despite their common chemical scaffold, these drugs differ in their pharmacokinetic and metabolic properties. In particular, they are biotransformed by different cytochrome P450 isoforms and also by different UDP-glucuronosyltransferase subtypes. The most important studies on the metabolic characteristics of several 1,4-benzodiazepines, carried out from 1998 onwards, are reported and briefly discussed in this review. Moreover, the analytical methods related to these studies are also described and commented upon and their most important characteristics are highlighted. Most methods are based on liquid chromatography, which provides wide applicability and good analytical performance granting high precision, accuracy and feasibility. Mass spectrometry is gaining widespread acceptance, particularly if the matrix is very complex and variable, such as human or animal blood. However, spectrophotometric detection is still used for this purpose and can grant sufficient selectivity and sensitivity when coupled to suitable sample pre-treatment procedures. A monograph is included for each of the following benzodiazepines: alprazolam, bromazepam, brotizolam, clotiazepam, diazepam, etizolam, flunitrazepam, lorazepam, midazolam, oxazepam and triazolam.

Marx CE; Trost WT; Shampine L; Behm FM; Giordano LA; Massing MW; Rose JE. Neuroactive steroids, negative affect, and nicotine dependence severity in male smokers. Psychopharmacology 186(3): 462-472, 2006. (87 refs.)

Nicotine administration alters neuroactive steroids in rodent models, and serum levels of the neuroactive steroid DHEAS (dehydroepiandrosterone sulfate) appear to be higher in smokers. These molecules may be relevant to tobacco addiction and affective symptoms. This study aims to investigate DHEAS, allopregnanolone, pregnenolone, and other steroids in male smokers to determine potential associations with nicotine dependence severity and negative affect. Allopregnanolone and pregnenolone serum levels were determined by gas chromatography/mass spectrometry, while DHEAS and other steroid levels were determined by radioimmunoassay in 28 male smokers. Correlational analyses were performed to determine potential associations with rating measures, including the Fagerstrom Test for Nicotine Dependence (FTND), the addiction subscale of the Ikard Smoking Motivation Questionnaire (ISMQ), the craving item on the Reasons to Smoke (RTS) Questionnaire, and the negative affect and craving subscales of the Shiffman-Jarvik Withdrawal Questionnaire. DHEAS levels were inversely correlated with the negative affect subscale of the Shiffman-Jarvik Withdrawal Questionnaire (r=-0.60, p=0.002) and the RTS craving item (r=-0.43, p=0.03), and tended to be inversely correlated with the FTND scores (r=-0.38, p=0.067) and the ISMQ addiction subscale (r=-0.38, p=0.059), adjusting for age. Allopregnanolone levels were positively correlated with cotinine levels (r=0.57, p=0.006); pregnenolone levels tended to be positively correlated with cotinine levels (r=0.40, p=0.066). DHEAS levels were inversely correlated with negative affect and craving measures, and may predict nicotine dependence severity. Allopregnanolone levels were positively correlated with cotinine levels, suggesting that this neuroactive steroid may be upregulated in smokers. Neuroactive steroids may represent novel smoking cessation agents.

Maurer HH; Sauer C; Theobald DS. Toxicokinetics of drugs of abuse: Current knowledge of the isoenzymes involved in the human metabolism of tetrahydrocannabinol, cocaine, heroin, morphine, and codeine. (review). Therapeutic Drug Monitoring 28(3): 447-453, 2006. (72 refs.)

This review summarizes the major metabolic pathways of the drugs of abuse, tetrahydrocannabinol, cocaine, heroin, morphine, and codeine, in humans including the involvement of isoenzymes. This knowledge may be important for predicting their possible interactions with other xenobiotics, understanding pharmaco-/toxicokinetic and pharmacogenetic variations, toxicological risk assessment, developing suitable toxicological analysis procedures, and finally for understanding certain pitfalls in drug testing. The detection times of these drugs and/or their metabolites in biological samples are summarized and the implications of the presented data on the possible interactions of drugs of abuse with other xenobiotics, ie, inhibition or induction of individual polymorphic and nonpolymorphic isoenzymes, discussed.

McCance-Katz EF; Rainey PM; Smith P; Morse GD; Friedland G; Boyarsky B et al. Drug interactions between opioids and antiretroviral medications: Interaction between methadone, LAAM, and Delavirdine. American Journal on Addictions 15(1): 23-34, 2006. (33 refs.)

Understanding the drug interactions between antiretrovirals and opioid therapies may decrease toxicities and enhance adherence with improved HIV outcomes in opioid-dependent individuals. The authors report the results of a clinical pharmacology study designed to determine whether significant pharmacokinetic and/or pharmacodynamic interactions occur between the non-nucleoside reverse transcriptase inhibitor, delavirdine (DLV), and either methadone or levo-alpha acetyl methadol (LAAM) (n = 40). DLV significantly decreased methadone clearance (p=.018) and increased the methadone elimination half-life ( p <.001) with a resultant increase in AUC of 19% and C(min)of 29%. The combined effect of DLV on the total concentration of LAAM and its active metabolites, norLAAM and dinorLAAM, was to significantly increase AUC by 43% (p <.001), C-max by 30% (p <.013), and C-min by 59% (p <.004) while decreasing T-max (p <.05). Cognitive deficits over the seven-day study period as measured by the Mini-Mental State Examination, opioid withdrawal symptoms as measured by the Objective Opioid Withdrawal Scale, or complaints of adverse symptoms were not observed. Methadone and LAAM did not affect DLV concentrations. The findings from this study show that DLV treatment in methadone- or LAAM-maintained individuals results in altered opioid pharmacokinetics with an increased exposure and potential risk for opioid toxicity with methadone or LAAM treatment and an increased risk of cardiac toxicity with concomitant LAAM and DLV administration.

McDonough PC; Levine B; Vorce S; Jufer RA; Fowler D. The detection of hydromorphone in urine specimens with high morphine concentrations. Journal of Forensic Sciences 53(3): 752-754, 2008. (4 refs.)

A previous study suggested that small amounts of morphine are metabolically converted to hydromorphone. In the present study, morphine positive urine specimens obtained from a postmortem laboratory and a random urinalysis program were tested for morphine, codeine, hydromorphone, hydrocodone, oxymorphone, and oxycodone to assess the possibility that small amounts of hydromorphone are produced from the metabolism of morphine. The opioids were analyzed by gas chromatography-mass spectrometry as their respective trimethylsilyl derivatives following solid phase extraction. The limit of detection for hydromorphone was 5 ng/mL. A total of 73 morphine positive urine specimens were analyzed, with morphine concentrations ranging from 131 to 297,000 ng/mL. Hydromorphone was present at a concentration >= 5 ng/mL in 36 of these specimens at concentrations ranging from 0.02% to 12% of the morphine concentration. Hydrocodone was not detected in these specimens at the assay detection limit of 25 ng/mL. These results support earlier work suggesting that the detection of hydromorphone in urine specimens does not necessarily mean that exogenous hydromorphone or hydrocodone was used.

Miller SC. Dextromethorphan psychosis, dependence and physical withdrawal. Addiction Biology 10(4): 325-327, 2005. (13 refs.)

As part of a synthesis of evidence regarding the abuse and addiction liability of dextromethorphan (DM), an over-the-counter cough medicine available in over 140 preparations, all uncommonly published case of dextromethorphan dependence (addiction) is described, with specific, rarely published complications. The individual was interviewed and several medical databases were also reviewed (Medline, 1966 -present; PubMed) for all content relating to the Keywords: dextromethorphan, abuse, dependence, cough medicine, addiction, withdrawal, psychosis. The patient evidenced history suggesting substance dependence, substance-induced psychosis and substance withdrawal in relation to DM. A literature review revealed that DM has specific serotonergic and sigma-1 opioidergic properties. Dextrolphan (DOR), the active metabolite of DM, has similar properties; however, DOR is a weaker sigma opioid receptor agonist, and a stronger NMDA receptor antagonist. DM and DOR display specific biological features of addiction, and are capable of inducing specific psychiatric sequelae. A specific, reproducible toxidropne with significant psychiatric effects occurred, when DM was abused at greater than indicated doses, with more profound and potentially life-threatening effects at even higher doses. DM withdrawal appears evident. DMs active metabolite, DOR, has pharmacodynamic properties and intoxication effects similar to dissociatives, and may be more responsible for the dissociative effect that this DM abuser sought. However, it is this same metabolite that may be fraught with the potentially life-threatening psychoses and dissociative-induced accidents, as well as addiction. While DM has been hypothesized as the most commonly abused dissociative, health-care providers seem largely unaware of its toxidrome and addiction liability.

Moolchan ET; Franken FH; Jaszyna-Gasior M. Adolescent nicotine metabolism: Ethnoracial differences among dependent smokers. Ethnicity & Disease 16(1): 239-243, 2006. (40 refs.)

Variations in nicotine metabolism are thought to contribute to differences in cigarette consumption between African Americans and Caucasian adult smokers. To investigate the potential mechanism of previously documented lower smoking rates among African American adolescent snickers seeking cessation treatment, we measured nicotine metabolite ratios as markers of the metabolic disposition of nicotine, which is generally considered to be under the influence of cylochrome P450 (CYP) 2A6. Plasma ratios of trans-3'-hydroxycotinine (3HC) to cotinine (COT) were examined in 92 cessation treatment-seeking adolescents (mean age 15.2 years, standard deviation [SD] 1.3, 69% female, 31% African American, mean Fagerstrom Test for Nicotine Dependence [FTND] 6.5, SD 1.6, mean years smoked 2.6, SD 1.6). Groups were similar in age, gender distribution, and mean FTND score. Analysis with independent t tests revealed significantly lower number of cigarettes per clay (CPD) (15.1, SD 7.6 vs 19.6, SD 8.0, P=.013) and nicotine metabolite ratios (0.27, SD 0.15 vs 0.35, SD 0.16, P=.026) in African-American compared to Caucasian adolescent smokers. Consistent with metabolic variation, mean COT/CPD ratio was significantly higher in African-American compared to Caucasian adolescents. Results remained statistically significant when comparing menthol smokers by ethnicity. These findings are consistent with those found among adult smokers and provide a putative mechanism for reported ethnoracial differences in adolescent cigarette consumption. Our results underscore the need for measures independent of consumption for determining degree of nicotine dependence and treatment selection across ethnicities, even among youths.

Mooney ME; Li ZZ; Murphy SE; Pentel PR; Le C; Hatsukami DK. Stability of the nicotine metabolite ratio in ad libitum and reducing smokers. Cancer Epidemiology, Biomarkers and Prevention 17(6): 1396-1400, 2008. (19 refs.)

Background: The ratio of two nicotine metabolites, cotinine and trans -3'-hydroxycotinine (3-HC), has been validated as a method of phenotyping the activity of the liver enzyme cytochrome P450 (CYP) 2A6 and, thus, the rate of nicotine metabolism. Our objective was to evaluate the correlates and stability of the 3-HC to cotinine ratio in ad libitum and reducing smokers, using nicotine replacement therapy (NRT), over a period of months. Methods: Smokers (n = 123, 94% Caucasian) participated in a smoking reduction study, where one-third of the sample smoked ad libitum for 8 weeks (Waitlist phase), before joining the rest of the participants for 12 weeks of cigarette reduction (Reduction phase) using NRT. Urinary nicotine, cotinine, and 3-HC were measured at each visit. Results: The baseline 3-HC to cotinine ratio was significantly but weakly correlated with cigarettes per day (r = 0.19), BMI (r = -0.27), and waking at night to smoke (r = 0.23). As assessed by repeated measure ANOVA, the 3-HC to cotinine ratio was stable in the Waitlist phase [coefficient of variation for 3 to 4 measurements, 38% (range, 5-110%)], whereas minor variation was noted in the Reduction phase [coefficient of variation for 3-5 measurements, 35% (range, 10-107%)]. Conclusions: In nonreducing ad libitum smokers, the 3-HC to cotinine ratio was generally stable, whereas during smoking reduction using NRT, some small variation was detected. Although the current findings are suggestive of the stability of the 3-HC to cotinine ratio in a predominantly Caucasian sample smoking freely or reducing smoking with NRT, additional research is needed in more diverse populations.

Moriya F; Hashimoto Y; Furumiya J. Nicotine and cotinine levels in body fluids of smokers who committed suicide. Forensic Science International 168(2-3): 102-105, 2007. (16 refs.)

Cigarette smoking is associated with a higher risk for suicide. The present study was conducted on the hypothesis that suicide smokers show higher nicotine and cotinine levels in blood and urine than non-suicide smokers. We determined nicotine and cotinine levels in blood and urine of 87 deceased individuals (18 suicides and 69 non-suicides) by gas chromatography. The smoking rate was 77.8% for individuals who committed suicide and 42.0% for those who did not commit suicide. Average nicotine and cotinine levels in blood were significantly higher in the suicide smokers than in the non-suicide smokers (nicotine: 93.2 +/- 46.6 ng/ml versus 25.8 +/- 14.4 ng/ml, p < 0.0001 and cotinine: 378 +/- 235 ng/ml versus 201 +/- 137 ng/ml, p < 0.005). Average levels of urinary nicotine and cotinine were also significantly higher in the suicide smokers than in the non-suicide smokers (nicotine: 1980 +/- 2210 ng/ml versus 394 +/- 376 ng/ml, p < 0.005 and cotinine: 1170 +/- 1330 ng/ml versus 414 290 ng/ml, p < 0.05). Twenty-six decedents were intoxicated with alcohol, and they included 7 suicides (7 smokers) and 19 non-suicides (15 smokers). Our data suggest that cigarette smokers who commit suicide smoke more heavily than other cigarette smokers.

Mort JR; Kruse HR. Timing of blood pressure measurement related to caffeine consumption. Annals of Pharmacotherapy 42(1): 105-110, 2008. (21 refs.)

OBJECTIVE: To determine whether patients should wait 30 minutes after caffeine consumption to have their blood pressure measured. DATA SOURCES: Literature was obtained by searching MEDLINE (1980-September 2007), International Pharmaceutical Abstracts (1980-September 2007), and the Cochrane Database of Systematic Reviews (1994-September 2007). Search terms included caffeine and blood pressure. Literature was a so obtained from citations in relevant articles. STUDY SELECTION AND DATA EXTRACTION: Articles that examined caffeine's acute effect on blood pressure were reviewed, with additional focus on caffeine tolerance and hypertensive status. DATA SYNTHESIS: Caffeine appears to affect blood pressure through adenosine receptor inhibition and an increased release of select neurotransmitters. Caffeine levels peak 30-120 minutes after oral intake and caffeine's half-life is 3-6 hours. The effect of caffeine on blood pressure has been examined for decades, with variable results depending on factors such as population examined (eg, hypertensive status, physical stressors, age) and study design (eg, acute effects, chronic ingestion, retrospective epidemiologic review). Caffeine tolerance diminishes the acute effect of caffeine on blood pressure, and hypertensive individuals are more susceptible to blood pressure changes. Reviews of caffeine's acute effect on blood pressure indicate changes of 3-15 mm Hg systolic and 4-13 mm Hg diastolic. Typically, blood pressure changes occur within 30 minutes, peak in 1-2 hours, and may persist for more than 4 hours. CONCLUSIONS: Having a patient abstain from caffeine for 30 minutes prior to blood pressure monitoring is not adequate to avoid caffeine's potential effects. An alternative approach to blood pressure monitoring would be to ask the patient about recent caffeine consumption and interpret the blood pressure reading based on this information. In addition, healthcare practitioners should provide education regarding caffeine's effects.

Mwenifumbo JC; Sellers EM; Tyndale RF. Nicotine metabolism and CYP2A6 activity in a population of black African descent: Impact of gender and light smoking. Drug and Alcohol Dependence 89(1): 24-33, 2007. (69 refs.)

Genetic variation in CYP2A6 (the main nicotine metabolizing enzyme) accounts for some, but not all, of the interindividual and interethnic variability in the rates of nicotine metabolism. We conducted a nicotine kinetic study in smokers and nonsmokers of black African descent (N = 190), excluding those with common genetic variants in CYP2A6, to investigate the association of demographic variables with CYP2A6 activity (3HC/COT ratio) and nicotine disposition kinetics (estimated nicotine AUC). An additional aim was to examine whether impaired CYP2A6 activity and/or nicotine disposition kinetics were associated with lower cigarette consumption in a population of light smokers (mean <= 10 cigarettes per day). We found that smokers had decreased nicotine metabolism (p < 0.05), that women had higher CYP2A6 activity (p < 0.01) and that, in non-elderly adults, age did not impact CYP2A6 activity (p = 0.65) or nicotine disposition kinetics (p = 0.06). Our study also demonstrated that neither current alcohol use nor current marijuana use was associated with altered CYP2A6 activity (p = 0.55 and 0.72, respectively) or nicotine disposition kinetics (p = 0.38 and 0.91, respectively). Despite the light cigarette consumption of the smokers (N = 94), higher CYP2A6 activity was associated with greater cigarette consumption (p < 0.005). These findings highlight the need for smoking status and gender to be considered when interpreting studies using nicotine.

Myers AL; Williams HE; Kraner JC; Callery PS. Identification of anhydroecgonine ethyl ester in the urine of a drug overdose victim. Journal of Forensic Sciences 50(6): 1481-1485, 2005. (36 refs.)

Toxicological evaluation of postmortem urine collected from a 41-year-old deceased white male detected anhydroecgonine ethyl ester (ethyl ecgonidine, AEEE), a transesterification product of smoked cocaine co-abused with ethanol. A solid phase extraction (SPE) method was used to extract cocaine, AEEE, and related metabolites from urine. SPE on a 1 mL urine sample from the decedent followed by GC-MS detected AEEE. Other metabolites identified by GC-MS included cocaine, cocaethylene, and anhydroecgonine methyl ester (AEME). To determine whether some or all of the AEEE was artifactually produced in the heated GC injector port, an alternative LC-MS method was developed. LC/MS following of AEEE detected in the urine was compared to SPE found at least 50 ng/mL of AEEE in the extract. The mass fragmentation (MS/MS and MS3) spectra of authentic, synthesized compound. AEEE is a potential additional forensic market for the co-abuse of smoked cocaine and ethanol.

Nakajima M. Smoking behavior and related cancers: The role of CYP2A6 polymorphisms. (review). Current Opinion in Molecular Therapeutics 9(6): 538-544, 2007. (76 refs.)

Smoking exerts complex central and peripheral nervous system, behavioral, cardiovascular, and endocrine effects in humans and is a primary risk factor for various cancers. Nicotine, a major constituent of tobacco, is the compound that is responsible for the development and maintenance of tobacco dependence. The absorbed nicotine is rapidly and extensively metabolized to inactive cotinine by CYP2A6 in human livers, which has a major impact on nicotine clearance. Progress has been made in understanding the relationship between the inter-individual variability in nicotine metabolism and genetic polymorphisms of CYP2A6. Recent findings have increased our knowledge concerning ethnic differences in the allele frequencies of the CYP2A6 variants, nicotine metabolism, and cancer risk. In this review, the potential associations between the CYP2A6 polymorphisms and smoking behavior or the risk of cancer are also discussed.

Nakamae T; Shinozuka T; Sasaki C; Ogamo A; Murakami-Hashimoto C; Irie W et al. Case report: Etizolam and its major metabolites in two unnatural death cases. Forensic Science International 182(1-3): E1-E6, 2008. (18 refs.)

A simultaneous analytical method for etizolam and its main metabolites (alpha-hydroxyetizolam and 8-hydroxyetizolam) in whole blood was developed using solid-phase extraction, TMS derivatization and ion trap gas chromatography tandem mass spectrometry (GC-MS/MS). Separation of etizolam, TMS derivatives of alpha-hydroxyetizolam and 8-hydroxyetizolam and fludiazepam as internal standard was performed within about 17 min. The inter-day precision evaluated at the concentration of 50 ng/mL etizolam, alpha-hydroxyetizolam and 8-hydroxyetizolam was evaluated 8.6, 6.4 and 8.0% respectively. Linearity occurred over the range in 5-50 ng/mL. This method is satisfactory for clinical and forensic purposes. This method was applied to two unnatural death cases suspected to involve etizolam. Etizolam and its two metabolites were detected in these cases.

Otani K; Ujike H; Sakai A; Okahisa Y; Kotaka T; Inada T et al. Reduced CYP2D6 activity is a negative risk factor for methamphetamine dependence. Neuroscience Letters 434(1): 88-92, 2008. (43 refs.)

Because methamphetamine (METH) is metabolized by CYP2D6 at the first step of hydroxylation and demethylation, it is possible that functional variants of CYP2D6 alter susceptibility to methamphetamine-induced dependence. We genotyped CYP2D6*1, *4, *5, *10, and *14 for 202 patients with METH dependence and 337 controls in a Japanese population and found a significant association of the CYP2D6 gene with METH dependence (p = 0.0299). The patients had fewer *10 and *14 alleles, which are hypofunction alleles, than the controls. CYP2D6 genotypes were divided into three phenotypes: extensive metabolizers, intermediate metabolizers, and poor metabolizers. There was no poor metabolizer among our Japanese subjects, and intermediate metabolizers of CYP2D6 were significantly fewer in methamphetamine-dependent subjects than in controls (p = 0.0212), with an odds ratio of 0.62 (95% confidence interval: 0.51-0.76). The present study demonstrated that reduced CYP2D6 activity was a negative risk factor for methamphetamine dependence.

Pan YM; Gao DQ; Yang WC; Cho H; Yang GF; Tai HH et al. Computational redesign of human butyrylcholinesterase for anticocaine medication. Proceedings of the National Academy of Sciences 102(46): 16656-16661, 2005. (52 refs.)

Molecular dynamics was used to simulate the transition state for the first chemical reaction step (TS1) of cocaine hydrolysis catalyzed by human butyrylcholinesterase (BChE) and its mutants. The simulated results demonstrate that the overall hydrogen bonding between the carbonyl oxygen of (-)-cocaine benzoyl ester and the oxyanion hole of BChE in the TS1 structure for (-)-cocaine hydrolysis catalyzed by A199S/S287G/A328W/Y332G BChE should be significantly stronger than that in the TS1 structure for (-)-cocaine hydrolysis catalyzed by the WT BChE and other simulated BChE mutants. Thus, the transition-state simulations predict that A199S/ S287G/A328W/Y332G mutant of BChE should have a significantly lower energy barrier for the reaction process and, therefore, a significantly higher catalytic efficiency for (-)-cocaine hydrolysis. The theoretical prediction has been confirmed by wet experimental tests showing an approximate to (456 +/- 41)-fold improved catalytic efficiency of A199S/S287G/A328W/Y332G BChE against (-)-cocaine. This is a unique study to design an enzyme mutant based on transition-state simulation. The designed BChE mutant has the highest catalytic efficiency against cocaine of all of the reported BChE mutants, demonstrating that the unique design approach based on transition-state simulation is promising for rational enzyme redesign and drug discovery.

Patterson F; Schnoll RA; Wileyto EP; Pinto A; Epstein LH; Shields PG et al. Toward personalized therapy for smoking cessation: A randomized placebo-controlled trial of bupropion. Clinical Pharmacology and Therapeutics 84(3): 320-325, 2008. (32 refs.)

We examined whether a pretreatment phenotypic marker of nicotine metabolism rate (NMR) predicts successful smoking cessation with bupropion. Smokers (N = 414) were tested for pretreatment NMR, based on the ratio of 3'-hydroxycotinine/cotinine derived during smoking, before entering a placebo-controlled randomized trial of bupropion plus counseling. At the end of the 10-week treatment phase, slow metabolizers (1st NMR quartile) had equivalent quit rates with placebo or bupropion (32%). Fast metabolizers (4th NMR quartile) had low quit rates with placebo (10%), and these were enhanced significantly by bupropion (34%). Smokers in the 2nd quartile (placebo: 25%, bupropion: 30%) and the 3rd quartile (placebo: 20%, bupropion: 30%) did not benefit significantly from bupropion. At the 6-month follow-up, the relationship between the NMR and quitting remained similar, but was no longer statistically significant. A pretreatment assessment of NMR may identify smokers who are most and least likely to benefit from treatment with bupropion for smoking cessation.

Pedersen-Bjergaard U; Reubsaet JLE; Nielsen SL; Pedersen-Bjergaard S; Perrild H; Pramming S et al. Psychoactive drugs, alcohol, and severe hypoglycemia in insulin-treated diabetes: Analysis of 141 cases. American Journal of Medicine 118(3): 307-310, 2005. (27 refs.)

By systematically screening for alcohol and drugs, we identified a psychoactive substance in one third of blood samples from diabetic patients with severe hypoglycemia. Episodes of severe hypoglycemia are often complicated by a temporary memory deficit, and exposure to illicit drugs and alcohol is generally underreported. Therefore, reliance on a patient's own testimony has limited value, and independent biochemical verification is important. In a previous series of severe hypoglycemia, alcohol intake has been reported in 4% to 19% of episodes, similar to the frequency of positive blood alcohol screens in our study (17%). We found that psychoactive drugs were present in blood screens with a similar frequency (18%) as alcohol, divided evenly between pharmaceutical and illicit agents. Perhaps drug-induced impairment of cognitive function lessens the awareness of the need for self-treatment of hypoglycemia. Some drugs affect carbohydrate metabolism or glucose counterregulation. Alternatively, use of drugs and increased risk of severe hypoglycemia may share a common cause, such as less meticulous self-care. Finally, chronic use or abuse of drugs may lead to behavioral changes, such as irregular eating habits, which may increase the risk of severe hypoglycemia. People with diabetes are educated to understand the relation between alcohol consumption and the risk of severe hypoglycemia and to avoid excessive alcohol intake. It is possible that the younger diabetic patients in this study have instead been attracted to use psychoactive drugs that were not known to cause hypoglycemia.

Pragst F; Herre S; Bakdash A. Poisonings with diphenhydramine: A survey of 68 clinical and 55 death cases. Forensic Science International 161(2-3): 189-197, 2006. (30 refs.)

The antihistaminic drug diphenhydramine (DPH) is mainly used as a sedative, hypnotic and antiemetic. In many countries it is over-the-counter available, very common, and generally regarded as a harmless drug. Sixty-eight non-fatal and 55 fatal poisonings with DPH alone or in combination with other drugs were investigated in the Institute of Legal Medicine of the University Hospital Charite between 1992 and 2004. The analytical investigations were performed by HPLC with photodiode array detector (HPLC-DAD). The DPH concentrations ranged from 0.5 to 8.9 mu g/mL in the non-fatal cases and from 0.3 to 119 mu g/mL in fatal cases. The intoxication symptoms stated during emergency admission were inconsistent, with somnolence, sedation and retardation on one hand and tachycardia, anticholinergic syndrome, agitation, hallucinations, confusion, tremor, convulsions, delirium and coma on the other. In three cases rhabdomyolysis occurred. A concentration above 5 mu g/mL can be regarded as potentially lethal. In many of the survivors the time course of the concentrations of DPH and the metabolites desmethyldiphenhydramine (DM-DPH) and diphenylmethoxyacetic acid (DPMA) were investigated. Whereas DM-DPH is present in blood from the very beginning because of the high first pass metabolism, DPMA is slowly formed over several metabolic steps. For this reason, the concentration ratio DPMA/DPH can be used for an approximate estimation of the time between drug intake and sampling in clinical cases or of the survival time after drug ingestion in death cases. In some of the deaths the concentrations in heart blood were much higher than in venous blood. This is explained mainly by agonal aspiration of the vomited gastric content. Besides the majority of suicidal cases also a case of child maltreatment and a case, in which the drug was forcibly administrated in a drug facilitated crime, were investigated. From the results it follows that diphenhydramine is not less poisonous than other prescribed hypnotics. However, despite the hallucinogenic effects, an abuse for recreational purposes was not observed until now.

Pucci L; Geppetti A; Maggini V; Lucchesi D; Rossi AM; Longo V. CYP1A2 F21L and F186L Polymorphisms in an Italian population sample. Drug Metabolism and Pharmacokinetics 22(3): 220-222, 2007. (9 refs.)

P450 cytochromes (CYPs) enzymes play a major role in variability of drug response and cancer susceptibility. In particular, up to 60- fold interindividual variation has been detected in the activity of CYP1A2, which is involved in the metabolism of caffeine, several drugs and various toxic and carcinogenic compounds. Aim of this study is to assess the frequency of CYP1A2 F21L and F186L polymorphisms (formerly CYP1A2* 2 and * 11 alleles), up to now found in Asiatic populations only. These variants were absent in 500 Italian healthy subjects. Therefore it can be suggested that the variation of CYP1A2-dependent metabolism in the Caucasian population is not related to these two CYP1A2 polymorphisms. Thus, this study supports the view that ethnicity is a relevant factor to be carefully considered in pharmacogenetic studies.

Ring HZ; Valdes AM; Nishita DM; Prasad S; Jacob P; Tyndale RF et al. Gene-gene interactions between CYP2B6 and CYP2A6 in nicotine metabolism. Pharmacogenetics and Genomics 17(12): 1007-1015, 2007. (32 refs.)

Objectives: CYP2A6 is the major enzyme involved in nicotine metabolism, yet large interindividual variations in the rate of nicotine metabolism exist within groups of individuals having the same CYP2A6 genotype. We investigated the influence of genetic variation in another potential nicotine-metabolizing enzyme, CYP2136, and its interaction with CYP2A6, on the metabolism of nicotine. Methods Two hundred and twelve healthy Caucasian adult twin volunteers underwent an intravenous infusion of stable isotope-labeled nicotine and its major metabolite, cotinine, for characterization of pharmacokinetic and metabolism phenotypes. Five CYP2B6 genetic polymorphisms causing amino acid substitutions (R22C, Q172 H, S259R, K262R, and R487C) were analyzed. Results We observed that the CYP2B6*6 haplotype (defined as having both Q172 H and K262R variants) was associated with faster nicotine and cotinine clearance, and that such associations were more prominent among individuals having decreased-activity CYP2A6 genotypes. Statistically significant interactions between CYP2B6 and CYP2A6 genotypes were observed (P < 0.003 for nicotine clearance and P < 0.002 for cotinine clearance). Conclusions Our results indicate that CYP2B6 genetic variation is associated with the metabolism of nicotine and cotinine among individuals with decreased CYP2A6 activity. Further investigation of the roles of CYP2B6 and the interaction between CYP2B6 and CYP2A6 genotypes in mediating nicotine dependence and tobacco-related diseases is merited.

Rubinstein ML; Benowitz NL; Auerback GM; Moscicki AB. Rate of nicotine metabolism and withdrawal symptoms in adolescent light smokers. Pediatrics 122(3): e643-e647, 2008. (28 refs.)

OBJECTIVES. The rate of nicotine metabolism may contribute to vulnerability in adolescents' transition from smoking initiation to addiction. The objectives of this study were to examine the associations between the rate of nicotine metabolism and cigarette consumption, addiction, and withdrawal symptoms in a sample of adolescent light smokers. PARTICIPANTS. Twenty adolescent smokers between 13 and 17 years old, who smoked between 1 and 6 cigarettes daily for >= 6 months, were recruited from several San Francisco Bay area schools and pediatric clinics from 2006 to 2007. METHODS. Participants underwent 24 hours of supervised tobacco abstinence. Serum was collected at baseline and at 24 hours for measurement of the nicotine metabolites cotinine and 3'-hydroxycotinine. Participants also completed self-report measures, which included smoking behavior, nicotine dependence, and withdrawal scales at baseline and 24 hours after baseline. The ratio of serum 3'-hydroxycotinine/cotinine (the nicotine metabolite ratio), a measure of the rate of nicotine metabolism, was computed by using measurements from the 24-hour serum samples. RESULTS. Participants were divided into 2 groups: faster metabolizers (3'-hydroxycotinine/cotinine ratio < 0.5; n = 5) and slower metabolizers (3'-hydroxycotinine/cotinine ratio < 0.5; n = 15). Faster metabolizers reported greater withdrawal symptoms after 24 hours of abstinence compared with slower metabolizers even after adjusting for the number of cigarettes smoked per day. The metabolite ratio was significantly correlated with self-described level of addiction. CONCLUSIONS. This is the first study to report a significant relationship between the rate of nicotine metabolism and withdrawal symptoms and self- reported addiction in adolescent light smokers. Given the association between withdrawal symptoms and nicotine addiction, adolescent smokers who are faster metabolizers of nicotine may be at greater risk for becoming addicted to nicotine compared with slower metabolizers.

Rush E; Schulz S; Obolonkin V; Simmons D; Plank L. Are energy drinks contributing to the obesity epidemic? Asia Pacific Journal of Clinical Nutrition 15(2): 242-244, 2006. (7 refs.)

The consumption of energy drinks containing sucrose and caffeine is increasing worldwide. Ten healthy women aged 18 to 22 years and fasted overnight were randomly allocated to a standardised dose of sucrose either as an "energy" drink (containing sucrose and caffeine) or lemonade on the first day and then crossed over to the alternative drink on a second day. For thirty minutes before and thirty minutes after drinking oxygen consumption and carbon dioxide production were measured in the resting subject breath-by-breath by indirect calorimetry and the rates of carbohydrate and fat oxidation calculated. Energy drink consumption apparently caused increased carbohydrate oxidation (P = 0.004) and reduced lipid oxidation (P = 0.004) compared to lemonade. The longer term effects of combined caffeine and sucrose intake, particularly in sedentary individuals, on metabolism and body fatness needs further examination.

Salaspuro VJ; Hietala JM; Marvola ML; Salaspuro MP. Eliminating carcinogenic acetaldehyde by cysteine from saliva during smoking. Cancer Epidemiology, Biomarkers & Prevention 15(1): 146-149, 2006. (25 refs.)

Tobacco smoking is one of the strongest risk factors not only for lung cancer but also for cancers of the upper gastrointestinal tract. Acetaldehyde has been shown to dissolve into the saliva during smoking and to be a local carcinogen in the human upper digestive tract. Cysteine can bind to acetaldehyde and eliminate its toxicity. We developed a tablet that releases cysteine into the oral cavity during smoking and could therefore be a potential chemopreventive agent against toxicity of tobacco smoke. In this study, the efficacy Of L-cysteine -containing tablets to reduce the carcinogenic acetaldehyde in the saliva during tobacco smoking was examined. Seven volunteers smoked five cigarettes. During every smoking period, each volunteer sucked a blinded tablet containing 0, 1.25, 2.5, 5, or 10 mg of L-cysteine. Acetaldehyde was analyzed from salivary samples gas chromatographically at 0, 5, and 10 minutes from the beginning of the smoking. All tablets containing L-Cysteine reduced highly significantly the salivary acetaldehyde; 5 mg Of L-cysteine was the minimum concentration to totally eliminate the acetaldehyde from saliva. The mean salivary acetaldehyde concentrations in samples collected immediately after smoking with 0, 1.25, 2.5, 5, or 10 mg of L-cysteine were 228 +/- 115 mu mol/L, 85 +/- 42 mu mol/L (P = 0.007), 9 +/- 7 mu mol/L, 0.09 +/- 0.2 mu mol/L, 0 +/- 0 mu mol/L (P < 0.001), respectively. In conclusion, carcinogenic acetaldehyde could be totally inactivated in the saliva during smoking by sucking tablet containing 5 mg of L-cysteine. Even a small reduction of the carcinogenicity of cigarette smoke could gain benefit at the population level. Hence, this finding warrants for further clinical trials for L-cysteine tablet in the prevention of upper digestive tract cancers in smokers.

Schilt T; Koeter MWJ; de Win MML; Zinkstok JR; van Amelsvoort TA; Schmand B et al. The effect of ecstasy on memory is moderated by a functional polymorphism in the cathechol-O-methyltransferase (COMT) gene. European Neuropsychopharmacology 19(2): 116-124, 2009. (57 refs.)

There is ample evidence for decreased verbal memory in heavy Ecstasy users. However, findings on the presence of a dose-response relation are inconsistent, possibly due to individual differences in genetic vulnerability. Catechol-O-methyltransferase (COMT) is involved in the catabolism of Ecstasy. Therefore, COMT gene polymorphisms may moderate this vulnerability. We prospectively assessed verbal memory in subjects with a high risk for future Ecstasy use, and compared 59 subjects after first Ecstasy use with 60 subjects that remained Ecstasy-naive. In addition, we tested the interaction effect of Ecstasy and the functional Val (158)met polymorphism on verbal memory. Met-allele carriers were somewhat more sensitive to the effects of Ecstasy on verbal learning than homozygous vol-subjects. After correction for the use of other substances this effect was no longer statistically significant. The findings suggest that the COMT gene moderates the negative effect of Ecstasy on memory, but also other drug use seems to play a role.

Schnoll RA; Patterson F; Lerman C. Treating tobacco dependence in women. Journal of Women's Health & Gender-based Medicine 16(8): 1211-1218, 2007. (53 refs.)

Tobacco dependence poses unique health risks for women (e. g., obstetrical and perinatal complications, cervical cancer), and compared with men, the rate of lung cancer among women has been steadily increasing over the past 50 years. However, the rate of decline in smoking rates in the United States over the past decade has been far slower for women than for men. Unfortunately, less than two thirds of physicians who care exclusively for women provide formal assistance to patients who smoke. Barriers to smoking cessation that are unique to women include concerns about weight gain and negative emotional reactions following cessation. Recent data suggest that timing in the menstrual cycle may influence quitting success. Outcomes may be poorer for women than for men treated with nicotine replacement therapies (NRT), possibly because women experience more severe withdrawal symptoms, report poorer compliance with NRT, and exhibit greater sensitivity to nonnicotine factors, such as the sight, smell, and sensations of smoking, compared with men. There is also evidence suggesting that women have significantly higher rates of nicotine metabolism than men, particularly when using oral contraceptives. In contrast, data suggest that nonnicotine pharmacotherapies, such as bupropion and varenicline, have equivalent efficacy for women and men, and behavioral treatments that focus on postcessation weight reduction and negative mood management may be particularly beneficial for women. Overall, additional research is needed to examine the potential effectiveness and safety of pharmacotherapies for pregnant women who smoke. Greater attention to the unique needs of female smokers may allow healthcare providers to optimize delivery of pharmacotherapy and behavioral counseling to aid their female patients to quit smoking.

Seeman JI; Carchman RA. The possible role of ammonia toxicity on the exposure, deposition, retention, and the bioavailability of nicotine during smoking. (review). Food and Chemical Toxicology 46(6): 1863-1881, 2008. (175 refs.)

A complete and rigorous review is presented of the possible effect(s) of ammonia on the exposure, deposition and retention of nicotine during smoking and the bioavailability of nicotine to the smoker. There are no toxicological data in humans regarding ammonia exposure within the context of tobacco smoke. Extrapolation from occupational exposure of ammonia to smoking in humans suggests minimal, non-toxicological effects, if any. No direct study has examined the effect of the ammonia on the total rate or amount of nicotine reaching the arterial bloodstream or brains of smokers. Machine-smoking methods have been reported which accurately quantify >99% of the nicotine in mainstream (MS) smoke for a wide variety of commercial and test cigarettes, including a series of experimental cigarettes having a range in MS smoke ammonia yields using the US Federal Trade Commission (FTC) protocol. However, the actual exposure of nicotine to smokers depends on their own smoking behavior. The nicotine ring system is relatively thermally stable. Protonated nicotine forms nicotine which evaporates before the nicotine ring system decomposes. The experimental data indicate that neither nicotine transfer from tobacco to MS smoke nor nicotine bioavailability to the smoker increases with an increase in any of the following properties: tobacco soluble ammonia, MS smoke ammonia, "tobacco pH" or "smoke pH" at levels found in commercial cigarettes. Gas phase nicotine deposits primarily in the mouth and upper respiratory tract. To the extent that ammonia increases the deposition of nicotine in the buccal cavity and upper respiratory tract during smoking, the total rate and amount of nicotine into the arterial bloodstream and to the central nervous system will decrease. Charged nicotine analogues are actively transported in a number of tissues. This active transport system appears to be insensitive to pH and the form of nicotine in the biological milieu, suggesting that protonated nicotine may be a substrate for active transport. Neither "smoke pH" of commercial cigarettes nor "smoke pH(eff)" nor the fraction of non-protonated nicotine in tobacco smoke particulate matter are useful, practical smoke parameters for providing understanding or predictability of nicotine bioavailability to smokers. Greater than 95% of both ammonia and nicotine are in the gas phase of environmental tobacco, and both are likely to deposit in the buccal cavity and upper respiratory tract following exposure.

Sikka R; Magauran B; Ulrich A; Shannon M. Bench to bedside: Pharmacogenomics, adverse drug interactions, and the cytochrome P450 system. Academic Emergency Medicine 12(12): 1227-1235, 2005. (71 refs.)

As physicians attempt to improve the quality of health care, one area of particular concern has been preventable medical errors from adverse drug interactions. The cytochrome P450 family of enzymes has been implicated in a large number of these preventable, adverse drug interactions. This report reviews the basic biochemistry and pharmacogenomics underlying the reactions catalyzed by the cytochrome P450 family of enzymes. An emphasis is placed on the phenotypic variations within a population and the resulting clinical effects. In addition, six members of the cytochrome P450 superfamily that are responsible for the metabolism of the majority of pharmaceutical agents are profiled in detail. These enzymes, CYP3A4, CYP2D6, CYP2C9, CYP2CI9, CYP2E1, and CYP1A2, are reviewed with regard to their phenotypic variation in the population and the resulting clinical and therapeutic implications.

Staack RF; Maurer HH. Metabolism of designer drugs of abuse. (review). Current Drug Metabolism 6(3): 259-274, 2005. (185 refs.)

Abuse of designer drugs is widespread among young people, especially in the so-called "dance club scene" or "rave scene", worldwide. Severe and even fatal poisonings have been attributed to the consumption of such drugs of abuse. However, in contrast to new medicaments, which are extensively studied in controlled clinical studies concerning metabolism, including cytochrome P450 isoenzyme differentiation, and further pharmacokinetics, designer drugs are consumed without any safety testing. This paper reviews the metabolism of new designer drugs of abuse that have emerged on the black market during the last years. Para-methoxyamphetamine (PMA), para-methoxymethamphetamine (PMMA) and 4-methylthioamphetamine (4-MTA), were taken into consideration as new "classical" amphetamine-derived designer drugs. Furthermore, N-benzylpiperazine (BZP), 1-(3, 4-methylenedioxybenzyl)piperazine (MDBP), 1-(3-trifluoromethylphenyl)piperazine (TFMPP), 1-(3-chlorophenyl)piperazine (mCPP) and 1-(4-methoxyphenyl)piperazine (MeOPP) were taken into consideration as derivatives of the class of piperazine-derived designer drugs, as well as alpha-pyrrolidinopropiophenone (PPP), 4'-methoxy-alpha-pyrrolidinopropiophenone (MOPPP), 3', 4'-methylenedioxy-alpha-pyrrolidinopropiophenone (MDPPP), 4'-methyl-alpha-pyrrolidinopropiophenone (MPPP), and 4'-methyl-alpha-pyrrolidinoexanophenone (MPHP) as derivatives of the class of alpha-pyrrolidinophenone-derived designer drugs. Papers describing identification of in vivo or in vitro human or animal metabolites and cytochrome P450 isoenzyme dependent metabolism have been considered and summarized.

Stamm LR. The top 20 myths of breath, blood, and urine tests. Part 1. The Champion 29(September): 20-25, 2005. (35 refs.)

This article explores disagreement among the experts and the myths commonly employed by courts, police, an prosecutors, and often accepted by defense lawyers in drunk driving cases, and the published scientific articles debunking those myths. In some case there is honest debate about the validity of the state's methods and theories. In other cases, the state's experts' conclusions are translated improperly by police and prosecutors, to the detriment of defendants. The point of this article not to comprehensively discuss every point of view, but to quote some of the published scientific articles that challenge the status quo.

Stevens VL; Bierut LJ; Talbot JT; Wang JC; Sun JZ; Hinrichs AL et al. Nicotinic receptor gene variants influence susceptibility to heavy smoking. Cancer Epidemiology, Biomarkers & Prevention 17(12): 3517-3525, 2008. (26 refs.)

Heavy smoking is a strong predictor of nicotine dependence, which is a major impediment to smoking cessation. Although both heavy smoking and nicotine dependence are highly heritable, previous attempts to identify genes influencing these phenotypes have been largely unsuccessful until very recently. We studied 1,452 heavy smokers (defined as smoking at least 30 cigarettes per day for at least 5 years) and 1,395 light smokers (defined as smoking < 5 cigarettes per day for at least 1 year) to investigate the association of common variants in nicotinic receptor subunit genes with smoking behavior. Compared with the most common allele, two separate groups of single nucleotide polymorphisms (SNP) in the CHRNA5-CHRNA3-CHRNB4 gene cluster were associated with heavy smoking with a very high statistical significance. One group of eight SNPs, which included a nonsynonymous SNP in the CHRNA5 gene, was in strong linkage disequilibrium and associated with increased risk of heavy smoking. A second group of SNPs not strongly correlated with the first was associated with decreased risk of heavy smoking. Analyses that combined both groups of SNPs found associations with heavy smoking that varied by > 2-fold. Our findings identify two loci in the CHRNA5-CHRNA3-CHRNB4 gene cluster that predict smoking behavior and provide strong evidence for the involvement of the alpha 5 nicotinic receptor in heavy smoking.

Strain EC. Pharmacology of buprenorphine. IN: Strain EC; Stitzer ML, eds. The Treatment of Opioid Dependence. Baltimore: Johns Hopkins University Press, 2006. pp. 213-229. (66 refs.)

Buprenorphine is a mixed agonist-antagonist opioid. The chapter reviews the pharmacology of buprenorphine, its actions at different opioid receptors, its absorption, metabolism, and excretion, half-life and duration of effects. The clinical features are summarized in terms of withdrawal suppression, analgesic effects, respiratory depression, cross tolerance, plus its subjective and cognitive/psychomotor effects. Also there is discussion of the pharmacologic rationale for combining buprenorphine and naloxone.

Strasser AA; Malaiyandi V; Hoffmann E; Tyndale RF; Lerman C. An association of CYP2A6 genotype and smoking topography. Nicotine & Tobacco Research 9(4): 511-518, 2007. (41 refs.)

Nicotine is metabolized into biologically inactive cotinine primarily by the cytochrome P450 enzyme CYP2A6. CYP2A6 genetic variations have been phenotypically grouped as slow, intermediate, and normal metabolizers. Slow metabolizers smoke fewer cigarettes daily and weekly, and have lower carbon monoxide (CO) and plasma nicotine levels, suggesting a reduced smoking rate compared with normal metabolizers. CYP2A6 also is involved in the metabolic activation of tobacco-specific procarcinogenic nitrosamines, such as 4-( methyl-nitrosamino)-1-(3-pyridyl)- 1-butanone (NNK) and 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). NNK is one of the most abundant and potent procarcinogens in cigarette smoke. The present study investigated the association of CYP2A6 genotype with smoking topography, a quantifiable measure of smoking behavior, in a sample of treatment-seeking smokers prior to treatment. Smoking topography measures indicative of quantity of smoke exposure - number of puffs, mean puff volume, and total puff volume - were the outcome variables. Covariates associated with smoking topography were included in the analyses. Results indicated that CYP2A6 genotype group had a significant effect on mean puff volume and total puff volume, but not number of puffs, such that slow metabolizers exhibited reduced puffing compared with others. Smokers having CYP2A6 variants resulting in low activity metabolize nicotine more slowly, and convert procarcinogen nitrosamines to carcinogens more slowly, than do normal metabolizers. The results from this study also suggest a behavioral mechanism that may account for reduced cancer risk in slow metabolizers.

Sulzer D; Sonders MS; Poulsen NW; Galli A. Mechanisms of neurotransmitter release by amphetamines: A review. (review). Progress in Neurobiology 75(6): 406-433, 2005. (253 refs.)

Amphetamine and substituted amphetamines, including methamphetamine, methylphenidate (Ritalin), methylenedioxymethamphetamine (ecstasy), and the herbs khat and ephedra, encompass the only widely administered class of drugs that predominantly release neurotransmitter, in this case principally catecholamines, by a non-exocytic mechanism. These drugs play important medicinal and social roles in many cultures, exert profound effects on mental function and behavior, and can produce neurodegeneration and addiction. Numerous questions remain regarding the unusual molecular mechanisms by which these compounds induce catecholamine release. We review current issues on the two apparent primary mechanisms - the redistribution of catecholamines from synaptic vesicles to the cytosol, and induction of reverse transport of transmitter through plasma membrane uptake carriers - and on additional drug effects that affect extracellular catecholamine levels, including uptake inhibition, effects on exocytosis, neurotransmitter synthesis, and metabolism.

Tutka P; Mosiewicz J; Wielosz M. Pharmacokinetics and metabolism of nicotine. (review). Pharmacological Reports 57(2): 143-153, 2005. (95 refs.)

Nicotine (NIC), the major constituent of tobacco, is responsible for the compulsive use of tobacco. Advances in understanding of the pharmacokinetics and metabolism of NIC have been made rapidly over the past decade. The application of highly sensitive gas chromatography/mass spectrometry led to the identification and quantitation of new NIC metabolites as well as characterization of new pathways of NIC biotransformation. This review summarizes findings from human and animal studies concerning NIC kinetics and biotransformation as well as describes the factors that influence these processes. Recently, large individual, racial and species differences in the metabolism of NIC have been well documented. The differences in the metabolism of NIC may be a result of genetic, environmental, and developmental host influences. We review the scientific evidence from studies that supports a role for genetic mechanisms responsible for variability in the profile and the rate of the NIC metabolism. Actually, the majority of the genetic studies focus on the characterization of the CYP2A6 gene polymorphism, and on determining the relationship between the phenotype of NIC metabolism and the genotype of the CYP2A6 gene. There is good evidence that genetic polymorphisms associated with NIC metabolism are an important factor responsible for susceptibility to NIC dependence. It is anticipated that genetic findings can lead to the identification of individuals at a greater risk for tobacco addiction and will be used for more effective treatment and prevention strategies to reduce smoking.

van Dam RM; Hu FB. Coffee consumption and risk of type 2 diabetes: A systematic review. (review). Journal of the American Medical Association 294(1): 97-104, 2005. (62 refs.)

Context: Emerging epidemiological evidence suggests that higher coffee consumption may reduce the risk of type 2 diabetes. Objective To examine the association between habitual coffee consumption and risk of type 2 diabetes and related outcomes. Data Sources and Study Selection We searched MEDLINE through January 2005 and examined the reference lists of the retrieved articles. Because this review focuses on studies of habitual coffee consumption and risk of type 2 diabetes, we excluded studies of type 1 diabetes, animal studies, and studies of short-term exposure to coffee or caffeine, leaving 15 epidemiological studies (cohort or cross-sectional). Data Extraction: Information on study design, participant characteristics, measurement of coffee consumption and outcomes, adjustment for potential confounders, and estimates of associations was abstracted independently by 2 investigators. Data Synthesis: We identified 9 cohort studies of coffee consumption and risk of type 2 diabetes, including 193 473 participants and 8394 incident cases of type 2 diabetes, and calculated summary relative risks (RRs) using a random-effects model. The RR of type 2 diabetes was 0.65 (95% confidence interval [CI], 0. 54-0.78) for the highest (>= 6 or >= 7 cups per day) and 0.72 (95% Cl, 0.62-0.83) for the second highest (4-6 cups per day) category of coffee-consumption compared with the lowest consumption category (0 or <= 2 cups per day). These associations did not differ substantially by sex, obesity, or region (United States and Europe). In the cross-sectional studies conducted in northern Europe, southern Europe, and Japan, higher coffee consumption was consistently associated with a lower prevalence of newly detected hyperglycemia, particularly postprandial hyperglycemia. Conclusions: This systematic review supports the hypothesis that habitual coffee consumption is associated with a substantially lower risk of type 2 diabetes. Longer-term intervention studies of coffee consumption and glucose metabolism are warranted to examine the mechanisms underlying the relationship between coffee consumption and type 2 diabetes.

Van Dorsten FA; Daykin CA; Mulder TPJ; Van Duynhoven JPM. Metabonomics approach to determine metabolic differences between green tea and black tea consumption. Journal of Agricultural and Food Chemistry 54(18): 6929-6938, 2006. (40 refs.)

The purpose of this study was to compare the effects of black and green tea consumption on human metabolism. Seventeen healthy male volunteers consumed black tea, green tea, or caffeine in a randomized crossover study. Twenty-four-hour urine and blood plasma samples were analyzed by NMR-based metabonomics, that is, high-resolution H-1 NMR metabolic profiling combined with multivariate statistics. Green and black tea consumption resulted in similar increases in urinary excretion of hippuric acid and 1,3-dihydroxyphenyl-2-O-sulfate, both of which are end products of tea flavonoid degradation by colonic bacteria. Several unidentified aromatic metabolites were detected in urine specifically after green tea intake. Interestingly, green and black tea intake also had a different impact on endogenous metabolites in urine and plasma. Green tea intake caused a stronger increase in urinary excretion of several citric acid cycle intermediates, which suggests an effect of green tea flavanols on human oxidative energy metabolism and/or biosynthetic pathways.

von Weymarn LB; Brown KM; Murphy SE. Inactivation of CYP2A6 and CYP2A13 during nicotine metabolism. Journal of Pharmacology and Experimental Therapeutics 316(1): 295-303, 2006. (39 refs.)

Nicotine is the major addictive agent in tobacco. The primary catalyst of nicotine metabolism in humans is CYP2A6. However, the closely related enzyme CYP2A13 is a somewhat better catalyst. CYP2A13 is an extrahepatic enzyme that is an excellent catalyst of the metabolic activation of the tobacco-specific carcinogen 4-(methylnitrosamine)- 1-(3- pyridyl)- 1-butanone (NNK). Here we report that both CYP2A6 and CYP2A13 were inactivated during nicotine metabolism. Inactivation of both enzymes was dependent on NADPH and increased with time and concentration. Alternate substrates for CYP2A6 and CYP2A13 protected these enzymes from inactivation. Inactivation of CYP2A13 was irreversible upon extensive dialysis and seems to be mechanism-based. The K-I of CYP2A13 inactivation by nicotine was 17 mu M, the rate of inactivation, k(inact), was 0.1 min(-1), and the t(1/2) was 7 min. However, the loss in enzyme activity occurred after nicotine metabolism was complete, suggesting that a secondary or possible tertiary metabolite of nicotine may be responsible. [5-H-3] Nicotine metabolism by CYP2A13 was monitored by radioflow high-pressure liquid chromatography during the course of enzyme inactivation; the major product was the Delta(1'(5')) iminium ion. However, cotinine was a significant metabolite even at short reaction times. The metabolism of the nicotine Delta 1('(5')) iminium ion to cotinine did not require the addition of aldehyde oxidase. CYP2A13 catalyzed this reaction as well as further metabolism of cotinine to 5'-hydroxycotinine, trans-3'-hydroxycotinine, and N-(hydroxy-methyl)-norcotinine as enzyme inactivation occurred. Studies are on-going to identify the metabolite responsible for nicotine-mediated inactivation of CYP2A13.

Voytek B; Berman SM; Hassid BD; Simon SL; Mandelkern MA; Brody AL et al. Differences in regional brain metabolism associated with marijuana abuse in methamphetamine abusers. (short communication). Synapse 57(2): 113-115, 2005. (14 refs.)

Wang JS; Markowitz JS; Donovan JL; DeVane CL. P-glycoprotein does not actively transport nicotine and cotinine. Addiction Biology 10(2): 127-129, 2005. (11 refs.)

The ABCB1 gene transporter P-glycoprotein (P-gp) exists in the blood - brain barrier (BBB) and placenta and limits many drugs passing through the BBB and placenta. Several recent studies have raised confounding results regarding the roles of P-gp in nicotine disposition. To ascertain this question, we examined the effects of nicotine and its major oxidative metabolite, cotinine, on ATPase activity using P-gp containing membranes, in which nicotine and cotinine-stimulated inorganic Pi was used as a marker of the binding affinity of nicotine and cotinine to P-gp. At concentrations ranging from 5 to 1000 mu M, both nicotine and cotinine produced modest stimulative effects on ATPase activity in the P-gp containing membrane. The Cl-int values of nicotine and cotinine were 0.01 and 0.007 minute(-1) x 10(-3), respectively. The positive control, verapamil, at concentrations ranging from 1 to 100 mu M, created apparent stimulative effects on ATPase activity, with a Cl-int value of 1.7 minute(-1) x 10(-3), consistent with previously reported results. The results of the current study suggest that nicotine and cotinine were not actively transported by P-gp out of the cells. The observed carrier-mediated nicotine transport in various cell lines may be mediated by other transporter proteins but not P-gp.

Webster LR. Pharmacogenetics in pain management: The clinical need. Clinics in Laboratory Medicine 28(4): 569-579, 2009. (57 refs.)

Genetic research heralds a new therapeutic approach to pain management. Increasing literature demonstrates individual genetic vulnerabilities to specific pain types and mechanisms, partially explaining differing responses to similar pain stimuli. Furthermore, analgesics demonstrate great variability among polymorphic genotypes. Family history and genotyping promise to play all important role ill future pain therapies. As advances continue ill the genetics of pain and analgesia, pharmacotherapy will depend more on all individualized, targeted approach and less on empiricism.

Williams JM; Ziedonis DM; Abanyie F; Steinberg ML; Foulds J; Benowitz NL. Increased nicotine and cotinine levels in smokers with schizophrenia and schizoaffective disorder is not a metabolic effect. Schizophrenia Research 79(2-3): 323-335, 2005. (48 refs.)

it has been hypothesized that smokers with schizophrenia take in more nicotine per cigarette than smokers without this disorder. This study examines this phenomenon by comparing the serum nicotine and cotinine levels in smokers with either schizophrenia or schizoaffective disorder compared to control smokers without mental illness. Serum cotinine and nicotine levels of smokers with schizophrenia or schizoaffective disorder were 1.3 times higher than control smokers (cotinine 291 versus 227 ng/mL; p=0.0115; nicotine 28 versus 21 ng/mL; p<0.001) despite smoking a similar number of cigarettes per day. Similar serum 3'-hydroxycotinine (3HC) to cotinine ratios in both groups indicate that this difference was not due to differences in the rate of metabolism of nicotine or cotinine. By examining serum nicotine and 3HC/cotinine ratios in addition to cotinine, this study expands upon previous research that relied on cotinine as an indirect indicator for nicotine intake. Our data support the hypothesis that the increased serum nicotine and cotinine levels observed are attributable to an increased nicotine intake per cigarette in smokers with schizophrenia as compared to those without mental illness.

Wolff K; Boys A; Rostami-Hodjegan A; Hay A; Raistrick D. Changes to methadone clearance during pregnancy. European Journal of Clinical Pharmacology 61(10): 763-768, 2005. (51 refs.)

Objective: Measurement of plasma methadone concentration to investigate the rate of clearance of methadone prescribed for heroin dependence in the first, second and third trimesters of pregnancy. A secondary objective was to evaluate the outcome of pregnancy. Methods: Longitudinal within subject study of nine pregnant opioid dependent subjects prescribed methadone at the Leeds Addiction Unit, an outpatient community based treatment centre. Plasma concentration versus time data for methadone was collected during each trimester and post-partum for our subjects. Data was available for the first and second trimesters for 4/9 cases. All but one of the subjects provided data during the third trimester and data post-partum was collected from three respondents. Measurements of methadone levels in plasma were carried out using high performance liquid chromatography (HPLC). Results: Trough mean plasma methadone concentrations reduced as the pregnancies progressed from 0.12 mg/L (first trimester) to 0.07 mg/L (third trimester). The weight-adjusted clearance rates gradually increased from a mean of 0.17 to 0.21 L/hr/kg during pregnancy, although patterns differed substantially between the nine women. An assessment of relative clearance of methadone using two patients for whom we have had all three CL values (trimester 1-3) demonstrated notable change of CL (P=0.056) over time. Eight of our subjects delivered (3 males), within two weeks of their due date the ninth (male) was premature (21 days). The mean length of gestation was 39.7 weeks (SD=10 days) and none of the neonates met criterion for 'low birth weight' mean 3094, SD 368 g). Five neonates spent time (0.5-28 days) in a special care baby unit (SCUBU) and 4 of these displayed signs of methadone withdrawal. Conclusions: General Practitioners and hospital doctors should recognise the significant benefits of prescribing methadone for heroin-dependent women during pregnancy. We recommend that if a pregnant opioid user complains of methadone withdrawal symptoms (i.e. that the methadone dose does not "hold" them) the prescribing clinician takes this observation seriously and considers a more detailed assessment. Further work on key factors undergoing changes during pregnancy accounting for differences in methadone metabolism in the mother, fetus and neonate are required.

Wurst FM; Dresen S; Allen JP; Wiesbeck G; Graf M; Weinmann W. Ethyl sulphate: A direct ethanol metabolite reflecting recent alcohol consumption. Addiction 101(2): 204-211, 2006. (37 refs.)

Background: Ethyl sulphate (EtS), a direct ethanol metabolite, appears to offer potential as a biomarker for recent alcohol consumption. Although its window of assessment is similar to that of ethyl glucuronide (EtG), there are differences between the two markers in their pathways for formation and degradation. Aims: (a) To assess the excretion of EtS compared to EtG and ethanol in drinking experiments with healthy volunteers, and (b) to elucidate the possibility of using the two metabolites for monitoring abstinence in substance use disorder patients during rehabilitation treatment. Design, setting, participants (a) Nine drinking experiments were performed by six healthy volunteers (two females, four males), with a mean age of 34.1 years (20-62), average oral intake of 0.2 g/kg ethanol (0.1-0.61), and having 74 spot urine samples. (b) Thirty-six substance abuse patients (mean age 41.9 years, 20-59; 22 males, 14 females) in a rehabilitation programme after withdrawal, producing 98 urine samples. Ethyl glucuronide and ethyl sulphate were measured using liquid chromatography tandem mass spectrometry (LC-MS/MS) using d(5)-EtG and d(5)-EtS, respectively, as an internal standard. Findings: (a) Volunteers: EtG and EtS were detectable for up to 36 hours and reached the limits of determination in urine at 20.6 hours and 21.2 hours (median), respectively, after ethanol intake. EtG-100 (standardized to a creatinine of 100 mg/dl) reached its maximum level at 2.8 hours and EtS-100 at 2.1 hours (median) after the beginning of the experiment. Of the ethanol ingested, 0.022% was excreted as EtS in one volunteer. Eight samples were positive for EtS only and six for EtG only. Spearman's rank correlation coefficients of 0.84 (P < 0.0001) between EtG and EtS and 0.87 (P < 0.0001) between EtG-100 and EtS-100 were found. (b) Patients: of the 98 urine samples evaluated, 27 were positive for EtS and of these only 20 were also positive for EtG. Spearman's rank correlation coefficients of 0.84 (P < 0.0001) between EtG and EtS and 0.82 (P < 0.0001) between EtG-100 and EtS-100 were found. Conclusions: The data from patients and volunteers suggest that the direct ethanol metabolite ethyl sulphate has the potential to serve as a biomarker of recent ethanol intake. Because EtG and EtS are formed via different pathways they might be used conjointly, thereby increasing sensitivity.

Yamada H; Ishii Y; Oguri K. Metabolism of drugs of abuse: Its contribution to the toxicity and the inter-individual differences in drug sensitivity. (review). Journal of Health Science 51(1): 1-7, 2005. (54 refs.)

Abuse of drugs remains a serious and world-wide problem. As exemplified by opioids, there are large inter-individual differences in the effects and toxicity of drugs. However, the mechanism underlying such inter-individual differences remains largely unknown. Since, in many cases, drug metabolism affects the effects of drugs, the different metabolic capacity of individuals may explain these inter-individual differences. In this review, we shall focus on drugs of abuse and survey briefly their metabolism and the enzymes involved. In addition, we shall discuss the putative origin of the inter-individual differences in sensitivity to drugs of abuse.

Yasuda SU; Zhang L; Huang SM. The role of ethnicity in variability in response to drugs: Focus on clinical pharmacology studies. Clinical Pharmacology and Therapeutics 84(3): 417-423, 2008. (36 refs.)

Ethnicity is one factor that may account for the observed differences in both pharmacokinetics (PK) and pharmacodynamics (PD) of drugs, resulting in variability in response to drug therapy. Given that the applicability of clinical study results to the treatment of an individual patient is a critical consideration in a physician's choice of drug therapy, drug development should seek to ensure that a clinical pharmacologic evaluation includes a population that is representative of the target therapeutic population. Ethnic diversity in drug response with respect to safety and efficacy and the resulting differences in recommended doses have been well described for some drugs. Some of these differential responses may be related to the pharmacogenomics of a particular drug. Pharmacogenomic techniques have recently enjoyed widespread use in studies of drug exposure and response. The clinical relevance of variability in drug response due to pharmacogenomics of drug-metabolizing enzymes was considered at a September 2004 workshop cosponsored by the US Food and Drug Administration (FDA), Johns Hopkins University, and the Pharmaceutical Research and Manufacturers of America (http: www.fda.gov/cder/Offices/OCPB/workshops.htm).

Yeo SE; Jentjens RLPG; Wallis GA; Jeukendrup AE. Caffeine increases, exogenous carbohydrate oxidation during exercise. Journal of Applied Physiology 99(3): 844-850, 2005. (57 refs.)

Both carbohydrate (CHO) and caffeine have been used as ergogenic aids during exercise. It has been suggested that caffeine increases intestinal glucose absorption, but there are also suggestions that it may decrease muscle glucose uptake. The purpose of the study was to investigate the effect of caffeine on exogenous CHO oxidation. In a randomized crossover design, eight male cyclists (age 27 +/- 2 yr, body mass 71.2 +/- 2.3 kg, maximal oxygen uptake 65.7 +/- 2.2 ml center dot kg(-1)center dot min(-1)) exercised at 64 +/- 3% of maximal oxygen uptake for,120 min on three occasions. During exercise subjects ingested either a 5.8% glucose solution (Glu; 48 g/h), glucose with caffeine (Glu+Caf, 48 g/h + 5 mg center dot kg(-1)center dot h(-1)), or plain water (Wat). The glucose solution contained trace amounts of [U-C-13]glucose so that exogenous CHO oxidation could be calculated. CHO and fat oxidation were measured by indirect calorimetry, and C-13 appearance in the expired gases was measured by continuous-flow IRMS. Average exogenous CHO oxidation over the 90- to 120-min period was 26% higher (P < 0.05) in Glu+Caf (0.72 +/- 0.04 g/min) compared with Glu (0.57 +/- 0.04 g/min). Total CHO oxidation rates were higher (P < 0.05) in the CHO ingestion trials compared with Wat, but they were highest when Glu+Caf was ingested (1.21 +/- 0.37, 1.84 +/- 0.14, and 2.47 +/- 0.23 g/min for Wat, Glu, and Glu+Caf, respectively; P, < 0.05). There was also a trend (P = 0.082) toward an increased endogenous CHO oxidation with Glu+Caf (1.81 +/- 0.22 g/min vs. 1.27 +/- 0.13 g/min for Glu and 1.12 +/- 0.37 g/min for Wat). In conclusion, compared with glucose alone, 5 mg center dot kg(-1)center dot h(-1) of caffeine coingested with glucose increases exogenous CHO oxidation, possibly as a result of an enhanced intestinal absorption.

Yerger VB; Malone RE. Melanin and nicotine: A review of the literature. (review). Nicotine & Tobacco Research 8(4): 487-498, 2006. (190 refs.)

The role of melanin in nicotine uptake and metabolism has received little attention. Because nicotine has been shown to accumulate in tissues containing melanin, exploring links between melanin and nicotine may provide additional clues to understanding smoking behavior and disease effects. To examine the scientific literature on the relationship between melanin and nicotine, we conducted a PubMed search. We also searched online archives of internal tobacco industry documents. We retrieved and reviewed 82 published research papers related to melanin and nicotine or melanin and metabolism of other drugs, and 150 relevant internal tobacco industry documents. The published literature suggests that nicotine may accumulate in human tissues containing melanin and this retention may increase melanin synthesis. Existing research on the relationship between melanin and nicotine lacks an adequate consideration of this relationship's potential impact, if any, on nicotine metabolism, level of nicotine dependence, and ability to quit smoking. Differential accumulation of nicotine in melanin-containing tissues could have implications for individuals with high levels of melanin.

Yokoyama A; Yokoyama T; Kumagai Y; Kato H; Igaki H; Tsujinaka T et al. Mean corpuscular volume, alcohol flushing, and the predicted risk squamous cell carcinoma of the esophagus in cancer-free Japanese men. Alcoholism: Clinical and Experimental Research 29(10): 1877-1883, 2005. (33 refs.)

Background: Because some of the causes of increased mean corpuscular volume (MCV) and esophageal squamous cell carcinoma (ESCC), including alcoholism, acetaldehyde exposure, smoking, and poor nutrition are common to both, macrocytosis has been used as a predictor of early ESCC in Japanese alcoholics. We examined whether this was also true in the Japanese general population. Methods: This study compared the MCV of 522 cancer-free Japanese men with his risk of ESCC as defined using drinking, smoking, dietary habits and aldehyde dehydrogenase-2 (ALDH2) genotype in a previous case-control study of ESCC involving them as control subjects. Results: MCV was significantly correlated with ESCC risk predicted by drinking combined with ALDH2 genotype, smoking, or fruit intake. Men at higher risk of ESCC were more frequent in the groups with higher MCV (p < 0.0001 for trend). The replies to a questionnaire about facial flushing in response to alcohol showed that the trend was more prominent in men with current/former flushing, a surrogate marker for inactive ALDH2, than in men with no flushing (p < 0.0001). In comparison with the mean risk of men with MCV <= 93 fl (lowest quartile), that of current/former flushing men with MCV >= 99 fl (highest quartile) was 6.35-fold higher, whereas that of never-flushing men with MCV >= 99 fl was 2.50-fold higher. No sensitivity and specificity of the combination of moderate-to-heavy drinking and either MCV 99 fl or current/former flushing, either 30+ pack-years or MCV >= 99 fl or either 30+ pack-years or current/former flushing for detection of high-risk persons ranking in the top 10%, was 85% and 84%, 94% and 76%, or 98% and 77%, respectively. Conclusions: MCV and alcohol flushing might be used to better select candidates to screen this high-mortality-rate cancer not only in alcoholics but also in nonalcoholic Japanese men.