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CORK Bibliography: Drug Metabolism

65 citations. January 2009 to present

Prepared: March 2012

Al-Ghananeem AM; Herman BH; Abbassi M; Yu E; Miotto K; O'Brien CP et al. Urine and plasma pharmacokinetics of lofexidine after oral delivery in opiate-dependent patients. American Journal of Drug and Alcohol Abuse 35(5): 311-315, 2009. (17 refs.)

Objectives: The objective of this study was to investigate lofexidine urine and plasma pharmacokinetics using three different dosing regimens in opioid dependent subjects. To date, there have been no published studies on lofexidine appearance and excretion in urine of opioid dependent subjects. Methods: Subjects were stabilized with 100 mg morphine sulphate on days 3-8 of the study. The dosing regimens of lofexidine hydrochloride were .8 mg twice a day (BID), 1.2 mg BID, or .8 mg three times a day (TID) on days 9 through 16 of the study. Plasma and urine samples were collected at appropriate time points. Area under the concentration-time curve (AUC), maximum concentration in plasma (C-max), time when maximum concentration was reached (T-max) and fraction excreted unchanged in urine (Fe) were calculated. Results: The average half-life obtained from all profiles was 12.1 +/- 6.3 hr. Steady-state (SS) was reached by study day 15. The plasma pharmacokinetic parameters for 1.2 mg BID and .8 mg TID dosing regimens did not seem to be different at steady state (day 15). T-max was not statistically significantly different across dosing regimens. Fe values ranged between .01% and 34% with high variability within the same dosing regimen. For the total dose of 2.4 mg/day the two dosing regimens that were evaluated, namely 1.2 mg BID and .8 mg TID, did not show a significant statistical difference in plasma and urine pharmacokinetic parameters. Conclusion: Although preliminary due to the limited number of subjects, these findings are the first to document lofexidine urine pharmacokinetics in opiate addicts using a highly sensitive liquid chromatography tandem mass spectrometric analysis.

Backhouse SH; Biddle SJH; Bishop NC; Williams C. Caffeine ingestion, affect and perceived exertion during prolonged cycling. Appetite 57(1): 247-252, 2011. (34 refs.)

Caffeine's metabolic and performance effects have been widely reported. However, caffeine's effects on affective states during prolonged exercise are unknown. Therefore, this was examined in the present study. Following an overnight fast and in a randomised, double-blind, counterbalanced design, twelve endurance trained male cyclists performed 90 min of exercise at 70% VO2 (max) 1 h after ingesting 6 mg kg(-1)BM of caffeine (CAF) or placebo (PLA). Dimensions of affect and perceived exertion were assessed at regular intervals. During exercise, pleasure ratings were better maintained (F-(3,F-38) = 4.99, P < 0.05) in the CAF trial compared to the PLA trial with significantly higher ratings at 15,30 and 75 min (all P < 0.05). Perceived exertion increased (F-(3,F-28) = 19.86, P < 0.01) throughout exercise and values, overall, were significantly lower (F-(1,F-11) = 9.26, P < 0.05) in the CAF trial compared to the PLA trial. Perceived arousal was elevated during exercise but did not differ between trials. Overall, the results suggest that a moderate dose of CAF ingested 1 h prior to exercise maintains a more positive subjective experience during prolonged cycling. This observation may partially explain caffeine's ergogenic effects.

Barnes AJ; Brunet BR; Choo RE; Mura P; Johnson RE; Jones HE et al. Excretion of methadone in sweat of pregnant women throughout gestation after controlled methadone administration. Therapeutic Drug Monitoring 32(4): 497-503, 2010. (32 refs.)

Sweat patches (n = 350) were collected throughout gestation from 29 opioid-dependent pregnant women participating in an outpatient methadone-assisted therapy program. Volunteers provided informed consent to participate in institutional review board-approved protocols. Methadone was eluted from sweat patches with sodium acetate buffer, followed by solid-phase extraction and quantification by gas chromatography mass spectrometry (limit of quantification >= 10 ng/patch). Methadone was present in all weekly patches (n = 311) in concentrations ranging from 10.2 to 12,129.7 nanograms per patch and in 92.3% of short-term patches (n = 39, worn for 12 or 24 hours) in concentrations up to 3303.9 nanograms per patch. Correlation between patch concentrations and total amount of drug administered (r = 0.224), and concentrations and duration of patch wear (r = 0.129) were both weak. Although there were large intra-and intersubject variations in sweat drug concentrations, sweat testing was an effective alternative technique to qualitatively monitor illicit drug use and simultaneously document methadone medication-assisted treatment.

Barnes AJ; De Martinis BS; Gorelick DA; Goodwin RS; Kolbrich EA; Huestis MA. Disposition of MDMA and metabolites in human sweat following controlled MDMA administration. Clinical Chemistry 55(3): 454-462, 2009. (34 refs.)

BACKGROUND: Understanding the excretion of 3,4-methylenedioxymethamphetamine (MDMA) and metabolites in sweat is vital for interpretation of sweat tests in drug treatment, criminal justice, and workplace programs. METHODS: Placebo, low (1.0 mg/kg), and high (1.6 mg/kg) doses of oral MDMA were given double-blind in random order to healthy volunteers (n = 15) with histories of MDMA use. Participants resided on the closed clinical research unit for up to 7 days after each dose. Volunteers wore PharmChek (R) sweat patches (n = 640) before, during, and after controlled dosing. Patches were analyzed by solid phase extraction and GC-MS for MDMA, methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxyamphetamine (HMA), and 4hydroxy-3-methoxymethamphetamine (HMMA). Limits of quantification (LOQ) were 2.5 ng/patch for MDMA and 5 ng/patch for HMA, HMMA, and MDA. RESULTS: MDMA was the primary analyte detected in 382 patches (59.7%), with concentrations up to 3007 ng/patch. MDA was detected in 188 patches (29.4%) at <172 ng/patch, whereas no HMMA or HMA was detected; 224 patches (35.0%) and 60 patches (9.4%) were positive for MDMA and MDA, respectively, at the 25-ng/patch threshold proposed by the Substance Abuse and Mental Health Services Administration. CONCLUSIONS: Sweat testing was shown to be an effective and reliable method for monitoring MDMA use in this controlled MDMA administration study. However, variability in sweat excretion suggests that results should be interpreted qualitatively rather than quantitatively. These data provide a scientific database for interpretation of MDMA sweat test results.

Benowitz NL. Pharmacology of nicotine: Addiction, smoking-induced disease, and therapeutics. (review). Annual Review of Pharmacology and Toxicology 49: 57-71, 2009. (88 refs.)

Nicotine sustains tobacco addiction, a major cause of disability and premature death. Nicotine binds to nicotinic cholinergic receptors, facilitating neurotransmitter release and thereby mediating the complex actions of nicotine in tobacco users. Dopamine, glutamate, and gamma aminobutyric acid release are particularly important in the development of nicotine dependence, and corticotropin-releasing factor appears to contribute to nicotine withdrawal. Nicotine dependence is highly heritable. Genetic studies indicate roles for nicotinic receptor subtypes, as well as genes involved in neuroplasticity and learning, in development of dependence. Nicotine is primarily metabolized by CYP 2A6, and variability in rate of metabolism contributes to vulnerability to tobacco dependence, response to smoking cessation treatment, and lung cancer risk. Tobacco addiction is much more common in persons with mental illness and substance abuse disorders, representing a high proportion of current smokers. Pharmacotherapeutic approaches to tobacco addiction include nicotine replacement, bupropion, and varenicline, the latter a selective nicotine receptor partial agonist.

Bruce RD; Altice FL; Moody DE; Morse GD; Andrews L; Lin SN et al. Pharmacokinetic interactions between buprenorphine/naloxone and once-daily lopinavir/ritonavir. Journal of Acquired Immune Deficiency Syndromes 54(5): 511-514, 2010. (13 refs.)

Background: This study was conducted to examine the pharmacokinetic interactions between buprenorphine/naloxone (BUP/NLX) and lopinavir/ritonavir (LPV/r) in HIV-seronegative subjects chronically maintained on BUP/NLX. Methods: This study was an open labeled pharmacokinetic study in twelve HIV-seronegative subjects stabilized on at least 3 weeks of BUP/NLX therapy. Subjects sequentially underwent baseline and steady-state pharmacokinetic evaluation of once-daily LPV/r (800/200 mg). Results: Compared to baseline values, BUP AUC0-24h (46.8 vs. 46.2 ng*hr/mL) and Cmax (6.54 vs. 5.88 ng/mL) did not differ significantly after achieving steady-state LPV/r. Similar analyses of norBUP, the primary metabolite of BUP, demonstrated no significant difference in norBUP AUC0-24 hours (73.7 vs. 52.7 ng.h/mL); however, Cmax (5.29 vs. 3.11 ng/mL) levels were statistically different (P < 0.05) after LPV/r administration. Naloxone concentrations were similarly unchanged for AUC0-24 hours (0.421 vs. 0.374 ng.hr/mL) and Cmax (0.186 vs. 0.186 ng/mL). Using standardized measures, no objective opioid withdrawal was observed. The AUC0-24 hours and Cmin of LPV in this study did not significantly differ from historical controls (159.6 vs. 171.3 mu g.hr/mL) and (2.3 vs. 1.3 mu g/mL). Conclusions: The addition of LPV/r to stabilized patients receiving BUP/NLX did not affect buprenorphine pharmacokinetics but did increase the clearance of norbuprenorphine. Pharmacodynamic responses indicate that the altered norbuprenorphine clearance did not lead to opioid withdrawal. Buprenorphine/naloxone and LPV/r can be safely coadministered without need for dosage modification.

Bruce RD; Moody DE; Fang WFB; Chodkowski D; Andrews L; Friedland GH. Tipranavir/ritonavir induction of buprenorphine glucuronide metabolism in HIV-negative subjects chronically receiving buprenorphine/naloxone. American Journal of Drug and Alcohol Abuse 37(4): 224-228, 2011. (34 refs.)

Background: Previous reports on the pharmacokinetic of tipranavir (TPV) and buprenorphine (BUP)/naloxone found that coadministration resulted in an 80% reduction in the area under the curve AUC of the primary BUP metabolite, norBUP, without any pharmacodynamic consequences. This study was conducted to characterize how tipranivir/ritonavir effects the glucuronide metabolites of BUP and may explain the reduction in the norBUP. Methods: HIV-seronegative subjects stabilized on at least 3 weeks of BUP/naloxone sequentially underwent baseline and steady-state pharmacokinetic evaluation of twice daily TPV 500 mg coadministered with ritonavir 200 mg (TPV/r). Results: Twelve subjects were enrolled and ten completed the study. The steady-state pharmacokinetics for BUP-3-glucuronide (BUP-3G) and norBUP-3-glucuronide (norBUP-3G) in the presence and absence of steady-state TPV/r were analyzed. The C(max) of BUP-3G was 8.78 +/- 5.23 ng/mL without TPV/r and increased to 12.7 +/- 11.7 after steady state of TPV/r was achieved. The AUC of BUP-3G was 31.1 +/- 19.4 (ng/mL) (h) without TPV/r and increased to 58. 6 +/- 49.5 after steady state of TPV/r was achieved (p = .0966). In contrast, steady-state norBUP-3G AUC(0-24 h) (p = .0216) and C(max) (p = .0088) were significantly decreased in the presence of steady-state TPV/r. Conclusions. and Scientific Significance: This study further elucidates the effects of TPV/r on glucuronidation. The current evaluation of glucuronide metabolites of BUP and norBUP are suggestive of combined inhibition of Uridine diphosphate (UDP)-glucuronosyltransferase of the 1A family and cytochrome P450 3A4 that spares UGT2B7 leading to a shunting of BUP away from production of norBUP and toward BUP-3G as seen by a statistically significant increase in the AUC of BUP-3G.

Chan KH; Hsu MC; Tseng CY; Chu WL. Famprofazone use can be misinterpreted as methamphetamine abuse. Journal of Analytical Toxicology 34(6): 347-353, 2010. (17 refs.)

Famprofazone, a major ingredient of Gewolen(r), is an analgesic that has been demonstrated to be metabolized to methamphetamine (MA) and amphetamine (AM) following administration. Therefore, a famprofazone user may be interpreted as an illicit MA abuser in Taiwan because the user's urine tested positive for MA. The purpose of this study was to investigate whether the concentration of MA metabolized from a single dose of Gewolen users would offend the official controlled substance regulation and be identified as MA-positive. Subjects (n = 6) received 25 mg of famprofazone and collected all urine specimens at certain timed intervals for 48 h after drug administration. The urine specimens were screened by immunoassay and then confirmed by gas chromatography-mass spectrometry (GC-MS). The highest concentration of amphetamines by immunoassay was 1954 ng/mL, and 18.8% of the urine specimens' amphetamines concentrations exceeded 500 ng/mL. The MA and AM concentrations by GC-MS analysis of these urine specimens ranged from 901 to 2670 ng/mL and 208 to 711 ng/mL, respectively. These urine specimens were interpreted as MA-positive (� 500 ng/mL MA and � 100 ng/mL AM), according to the official test methods of Taiwan. The MA positive results appeared within 2-34 h. It is therefore clearly possible to misinterpret the legitimate famprofazone user as an MA abuser in Taiwan.

Cherner M; Bousman C; Everall I; Barron D; Letendre S; Vaida F et al. Cytochrome P450-2D6 extensive metabolizers are more vulnerable to methamphetamine-associated neurocognitive impairment: Preliminary findings. Journal of the International Neuropsychological Society 16(5): 890-901, 2010. (71 refs.)

While neuropsychological deficits are evident among methamphetamine (meth) addicts, they are often unrelated to meth exposure parameters such as lifetime consumption and length of abstinence. The notion that some meth users develop neuropsychological impairments while others with similar drug exposure do not, suggests that there may be individual differences in vulnerability to the neurotoxic effects of meth. One source of differential vulnerability could come from genotypic variability in metabolic clearance of meth, dependent on the activity of cytochrome P450-2D6 (CYP2D6). We compared neuropsychological performance in 52 individuals with a history of meth dependence according with their CYP2D6 phenotype. All were free of HIV or hepatitis C infection and did not meet dependence criteria for other substances. Extensive metabolizers showed worse overall neuropsychological performance and were three times as likely to be cognitively impaired as intermediate/poor metabolizers. Groups did not differ in their demographic or meth use characteristics, nor did they evidence differences in mood disorder or other substance use. This preliminary study is the first to suggest that efficient meth metabolism is associated with worse neurocognitive outcomes in humans, and implicates the products of oxidative metabolism of meth as a possible source of brain injury.

Cruickshank CC; Dyer KR. A review of the clinical pharmacology of methamphetamine. (review). Addiction 104(7): 1085-1099, 2009. (182 refs.)

To examine the literature regarding clinical pharmacokinetics, direct effects and adverse clinical outcomes associated with methamphetamine use. Relevant literature was identified through a PubMed search. Additional literature was obtained from relevant books and monographs. The mean elimination half-life for methamphetamine is approximately 10 hours, with considerable inter-individual variability in pharmacokinetics. Direct effects at low-to-moderate methamphetamine doses (5-30 mg) include arousal, positive mood, cardiac stimulation and acute improvement in cognitive domains such as attention and psychomotor coordination. At higher doses used typically by illicit users (>= 50 mg), methamphetamine can produce psychosis. Its hypertensive effect can produce a number of acute and chronic cardiovascular complications. Repeated use may induce neurotoxicity, associated with prolonged psychiatric symptoms, cognitive impairment and an increased risk of developing Parkinson's disease. Abrupt cessation of repeated methamphetamine use leads to a withdrawal syndrome consisting of depressed mood, anxiety and sleep disturbance. Acute withdrawal lasts typically for 7-10 days, and residual symptoms associated with neurotoxicity may persist for several months.

Faessel HM; Obach RS; Rollema H; Ravva P; Williams KE; Burstein AH. A review of the clinical pharmacokinetics and pharmacodynamics of varenicline for smoking cessation. (review). Clinical Pharmacokinetics 49(12): 799-816, 2010. (68 refs.)

Varenicline tartrate (Chantix (R)/Champix (R)) is a selective partial agonist of the alpha(4)beta(2) nicotinic acetylcholine receptor and is approved as an aid to smoking cessation. The usual oral dosage in adults is 1 mg twice daily for 12 weeks, with an initial titration week. Several clinical pharmacology studies have characterized the pharmacokinetics of varenicline in adult smokers aged 18-55 years, elderly smokers and nonsmokers aged >= 65 years, adolescent smokers aged 12-17 years and subjects with impaired renal function. Varenicline exhibits linear pharmacokinetics following single- and multiple-dose administration of up to 3 mg/da. After oral administration absorption is virtually complete and systemic availability is high Oral bioavailability is not affected by food or time-of-day dosing, maximum plasma drug concentrations typically occur within 3-4 hours after dosing. Protein binding of varenicline is low (<= 20%) and independent of age and renal function. Varenicline is almost exclusively excreted unchanged in urine, primarily through glomerular filtration, with some component of active tubular secretion via human organic cation transporter, hOCT-2. Varenicline does not undergo significant metabolism and is not metabolized by hepatic microsomal cytochrome P450 (CYP) enzymes. Consistent with an elimination half-life of similar to 24 hours, steady-state conditions are reached within 4 days of repeat dosing. There are no remarkable differences between smokers and nonsmokers in metabolism or excretion of varenicline. In vitro, varenicline does not inhibit nor induce the activity of the major CYP enzymes. No clinically meaningful pharmacokinetic drug interactions are observed when varenicline is coadministered with the narrow therapeutic index drugs warfarin or digoxin, the smoking cessation therapies bupropion or transdermal nicotine, and the renally secreted drugs cimetidine or metformin. An Integrated model-based analysis of varenicline pharmacokinetics across several studies in adult smokers further showed that renal function was the clinically important factor leading to interindividual variability in systemic exposure to varenicline. Although no dose adjustment is required for subjects with mild to moderate renal impairment, a dose reduction to 1 mg/day is indicated for subjects with severe renal insufficiency. After accounting for renal function, there was no apparent effect of age, sex or race on varenicline pharmacokinetics. Varenicline pharmacokinetics in adolescents were generally comparable to those in adults, the bodyweight effect, which resulted in greater exposure in individuals of smaller body size (weighing 55 kg), was adequately offset by administration of half the dose recommended in adults (It is, however, important to note that varenicline is currently not approved for use in smokers aged under 18 years). Exposure-response analyses relating individual-specific drug exposure to clinical responses consistently showed that the end-of-treatment abstinence rate in adult smokers increased linearly with increasing varenicline exposure, the 1 mg twice-daily dose regimen was reliably associated with greater exposure and an increased probability of achieving a stable quit within 1 year from the start of treatment. Nausea was the single most frequently reported adverse event in varenicline clinical trials, with an incidence that was sex-related and Increased with varenicline exposure. In all, the predictable pharmacokinetic properties and straightforward dispositional profile of varenicline simplify its use in clinical practice

Fonseca F; de la Torre R; Diaz L; Pastor A; Cuyas E; Pizarro N et al. Contribution of cytochrome P450 and ABCB1 genetic variability on methadone pharmacokinetics, dose requirements, and response. PLoS ONE 6(5): e19527, 2011. (76 refs.)

Although the efficacy of methadone maintenance treatment (MMT) in opioid dependence disorder has been well established, the influence of methadone pharmacokinetics in dose requirement and clinical outcome remains controversial. The aim of this study is to analyze methadone dosage in responder and nonresponder patients considering pharmacogenetic and pharmacokinetic factors that may contribute to dosage adequacy. Opioid dependence patients (meeting Diagnostic and Statistical Manual of Mental Disorders, [4(th) Edition] criteria) from a MMT community program were recruited. Patients were clinically assessed and blood samples were obtained to determine plasma concentrations of (R, S)-, (R) and (S)-methadone and to study allelic variants of genes encoding CYP3A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, and P-glycoprotein. Responders and nonresponders were defined by illicit opioid consumption detected in random urinalysis. The final sample consisted in 105 opioid dependent patients of Caucasian origin. Responder patients received higher doses of methadone and have been included into treatment for a longer period. No differences were found in terms of genotype frequencies between groups. Only CYP2D6 metabolizing phenotype differences were found in outcome status, methadone dose requirements, and plasma concentrations, being higher in the ultrarapid metabolizers. No other differences were found between phenotype and responder status, methadone dose requirements, neither in methadone plasma concentrations. Pharmacokinetic factors could explain some but not all differences in MMT outcome and methadone dose requirements.

Ghazi AM; Salhab AS; Arafat TA; Irshaid YM. Effect of mint drink on metabolism of nicotine as measured by nicotine to cotinine ratio in urine of Jordanian smoking volunteers. Nicotine & Tobacco Research 13(8): 661-667, 2011. (18 refs.)

Introduction: Variation in nicotine metabolism may be due to genetic alterations in CYP 2A6, environmental factors, and diet. The purpose of this research was to evaluate mint drink effect on nicotine metabolism as judged by nicotine/cotinine ratio in urine of Jordanian smokers. Methods: Twenty-four Jordanian smoker volunteers were allocated randomly into two groups. They either received mint drink 3 times a day for 1 week during the mint drink period or avoided menthol-containing products and mint drink for 1 week during the off-menthol period. One group treatment sequence was mint drink, off-menthol, while the other group treatment was off-menthol, mint drink. Early morning urine samples were collected at baseline and at the end of each period. Samples were analyzed by liquid chromatography-mass spectrometry for the nicotine and cotinine concentrations. Nicotine/cotinine ratio was calculated and compared among the different periods for each participant using the paired t test. Results: All participants showed a consistent pattern of higher nicotine/cotinine ratios during mint drink compared with off-menthol periods, although to a variable extent. Mean nicotine/cotinine ratio during mint drink for all participants (1.327 +/- 0.707) was higher than that during off-menthol (0.993 +/- 0.547). Paired t test statistical analysis revealed a p < .0001. The mean difference in nicotine/cotinine ratio between the two periods was (-0.335), and the 95% confidence interval of the mean difference was (-0.451)-(-0.219). Conclusion: Mint drink increased nicotine/cotinine ratio in urine, suggesting a reduction in conversion of nicotine to cotinine.

Grata E; Perrenoud L; Saugy M; Baume N. SARM-S4 and metabolites detection in sports drug testing: A case report. Forensic Science International 213(1-3): 104-108, 2011. (21 refs.)

Recently, pharmaceutical industry developed a new class of therapeutics called Selective Androgen Receptor Modulator (SARM) to substitute the synthetic anabolic drugs used in medical treatments. Since the beginning of the anti-doping testing in sports in the 1970s, steroids have been the most frequently detected drugs mainly used for their anabolic properties. The major advantage of SARMs is the reduced androgenic activities which are the main source of side effects following anabolic agents' administration. In 2010, the Swiss laboratory for doping analyses reported the first case of SARMs abuse during in-competition testing. The analytical steps leading to this finding are described in this paper. Screening and confirmation results were obtained based on liquid chromatography tandem mass spectrometry (LCMS/MS) analyses. Additional information regarding the SARM S-4 metabolism was investigated by ultra high-pressure liquid chromatography coupled to quadrupole time-of-flight mass spectrometer (UHPLC-QTOF-MS).

Gratziou C. Respiratory, cardiovascular and other physiological consequences of smoking cessation. (review). Current Medical Research and Opinion 25(2): 535-545, 2009. (73 refs.)

Background: Smoking cessation is associated with substantial reductions in tobacco-related morbidity and mortality. Based on the current literature, the beneficial effects of quitting are particularly evident on pulmonary and cardiovascular function, but the negative physiological effects of cessation are less well documented. Scope: The objective of this article was to review systematically data on the physiological effects of smoking cessation. Articles based upon clinical trials, randomised controlled trials and meta-analyses were selected from titles and abstracts obtained via a MEDLINE search ( May 2003-May 2008). Additional studies were identified from the bibliographies of reviewed literature. Findings: Smoking cessation is associated with improved lung function and a reduction in the presence and severity of respiratory symptoms. These changes, apparent within months of quitting, are sustained with long-term abstinence. The underlying pathophysiologies of smoking-induced airway inflammation and endothelial dysfunction are partially reversed following cessation in healthy ex-smokers, but not in those with chronic obstructive pulmonary disease. Smoking cessation is also associated with substantially improved cardiovascular function and reduced risk of primary and secondary cardiovascular morbidity and mortality. Although the overall long-term health benefits are unquestionable, smoking cessation is also associated with other possible undesirable short-term physiological effects such as weight gain, hypertension, constipation and mouth ulcers; and altered activity of the enzyme cytochrome P450 1A2 (CYP1A2), which metabolises many commonly used drugs. Conclusion: The negative physiological effects of smoking cessation may adversely affect a smoker's attempt to quit, and physicians should provide their smoking patients with motivation and regular encouragement and support when attempting to quit, whilst educating them on the health benefits of abstinence. Additionally, since cigarette smoke is a potent inducer of CYP1A2, patients attempting to quit smoking should have their dosages of drugs metabolised by this enzyme closely monitored.

Hammons G. What is the biological fate of mentholated cigarette smoking? (editorial. Addiction 105(Supplement 1): 8-10, 2010. (19 refs.)

Ho MK; Mwenifumbo JC; Al Koudsi N; Okuyemi KS; Ahluwalia JS; Benowitz NL et al. Association of nicotine metabolite ratio and CYP2A6 genotype with smoking cessation treatment in African-American light smokers. Clinical Pharmacology and Therapeutics 85(6): 635-643, 2009. (48 refs.)

Cytochrome P450 2A6 (CYP 2A6) is the main nicotine (NI C)-metabolizing enzyme in humans. We investigated the relationships between CYP2A6 genotype, baseline plasma trans-3'-hydroxycotinine/cotinine (3HC/COT) (a phenotypic marker of CYP 2A6 activity), and smoking behavior in African-American light smokers. Cigarette consumption, age of initiation, and dependence scores did not differ among 3HC/COT quartiles or CYP2A6 genotype groups. Slow metabolizers (SMs; both genetic and phenotypic) had significantly higher plasma NI C levels, suggesting that cigarette consumption was not reduced to adjust for slower rates of NI C metabolism. Individuals in the slowest 3HC/COT quartile had higher quitting rates with both placebo and NIC gum treatments (odds ratio 1.85, 95% confidence interval (CI) 1.08-3.16, P = 0.03). Similarly, the slowest CYP2A6 genotype group had higher quitting rates, although this trend did not reach significance (odds ratio 1.61, 95% CI 0.95-2.72, P = 0.08). The determination of the 3HC/COT ratio, and possibly CYP2A6 genotype, may be useful in the future for personalizing the choice of smoking cessation treatment in African-American light smokers.

Hantson P; Capron A; Wallemacq P. Toxicokinetics of cocaine and metabolites in a body-packer becoming symptomatic. Journal of Forensic and Legal Medicine 18(8): 385-387, 2011. (8 refs.)

Life-threatening complications may occur in body-packers and the rupture of a single packet containing cocaine may lead to fatality. We report the case of a 35-year-old body-packer who developed at the airport clinical signs of cocaine toxicity. There was evidence of bowel obstruction. The plasma concentration of cocaine, benzoylecgonine (BZE) and ecgonine methyl ester (EME) was determined I h after symptoms onset, during surgery and postoperative period. The measured peak value at 1 h was 594 ng/ml for cocaine, 9423 ng/ml for BZE and 3261 ng/ml for EME. We confirm the following order BZE > EME > cocaine for peak plasma concentrations. A rebound in plasma levels was found during surgery, together with electrocardiographic changes. A total of 107 packets were eliminated, and the patient survived.

Hoiseth G; Morini L; Polettini A; Christophersen A; Morland J. Blood kinetics of ethyl glucuronide and ethyl sulphate in heavy drinkers during alcohol detoxification. Forensic Science International 188(1-3): 52-56, 2009. (28 refs.)

Studies of ethyl glucuronide (EtG) blood kinetics have so far been performed on healthy volunteers with ingestion of low to moderate doses of ethanol. These data are not necessarily transferable to heavy drinkers where the consumed doses of ethanol are much higher. The aim of this study was to investigate the pharmacokinetics of EtG and ethyl sulphate (EtS) in blood in heavy drinkers after termination of alcohol ingestion. Sixteen patients from an alcohol withdrawal clinic were included directly after admission. Time of end of drinking, estimated daily intake of ethanol (EDI) and medical history were recorded. Three to five blood samples over 20-43 h were collected from each patient subsequent to admission. The median EDI was 172 g (range 60-564). The first sample was collected median 2.5 h after end of drinking (range 0.5-23.5). Two patients had levels of EtG and EtS below LOQ in all samples, the first collected 19.25 and 23.5 h after cessation of drinking, respectively. Of the remaining 14 patients, one subject, suffering from both renal and hepatic disease, showed concentrations of EtG and EtS substantially higher than the rest of the material. This patient's initial value of EtG was 17.9 mg/L and of EtS 5.9 mg/L, with terminal elimination half lives of 11.9 h for EtG and 12.5 h for EtS. Among the remaining 13 patients, the initial median values were 0.7 g/L (range 0-3.7) for ethanol, 1.7 mg/L (range 0.1-5.9) for EtG and 0.9 mg/L (range 0.1-1.9) for EtS. Elimination occurred with a median half-life of 3.3 h for EtG (range 2.6-4.3) and 3.6 h for EtS (range 2.7-5.4). In conclusion, elimination of EtG in heavy drinkers did not significantly differ from healthy volunteers, and EtS appeared to have similar elimination rate. In the present work, there was one exception to this, and we propose that this could be explained by the patient's renal disease, which would delay excretion of these conjugated metabolites.

Holmquist GL. Opioid metabolism and effects of cytochrome P450. (review). Pain Medicine 10(Supplement 1): S20-S29, 2009. (62 refs.)

Over the past 10-20 years researchers have enhanced our understanding of the metabolism and risk of drug interactions of numerous medications utilized by patients with pain conditions. Pain patients often are prescribed multiple medications that can inhibit or induce specific cytochrome P450 (CYP450) enzymes. This review will focus on the effect of the CYP450 enzyme system metabolism on opioid agents codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, and oxymorphone, as well as the potential effect of these opioids on the metabolism of other medications and vice versa.

Hunault CC; van Eijkeren JCH; Mensinga TT; de Vries I; Leenders MEC; Meulenbelt J. Disposition of smoked cannabis with high Delta(9)-tetrahydrocannabinol content: A kinetic model. Toxicology and Applied Pharmacology 246(3): 148-153, 2010. (26 refs.)

Introduction: No model exists to describe the disposition and kinetics of Inhaled cannabis containing a high THC dose. We aimed to develop a kinetic model providing estimates of the THC serum concentrations after smoking cannabis cigarettes containing high THC doses (up to 69 mg THC). Methods. Twenty-four male non-daily cannabis users smoked cannabis cigarettes containing 293 mg, 49 1 fig, and 69 4 mg THC Blood samples were collected over a period of 0-8 h and serum THC concentrations were measured. A two-compartment open model was fitted on the individual observed data. Results: Large inter-individual variability was observed in the pharmacokinetic parameters. The median pharmacokinetic parameters generated by the model were C-max = 175 ng/mL, T-max = 14 min, and AUC(0-8h) = 8150 ng x min/mL for the 69 4 mg THC dose Median model results show an almost linear dose response relation for C-max/Dose = 2.8 x 10(-6)/mL and AUC(0-8h)/Dose = 136 x 10(-6) min/mL. However, for increasing dose level, there was a clear decreasing trend C-max/Dose = 3 4, 2.6 and 2 5 x 10(-6)/mL and AUC(0-8h)/Dose = 157, 133 and 117 x 10(-6) min/mL for the 29 3, 49.1 and 69 4 mg dose, respectively. Within the restriction of 8 h of observation, the apparent terminal half life of THC was 150 min. Conclusion: The model offers insight into the pharmacokinetics of THC in recreational cannabis users smoking cannabis containing high doses of THC mixed with tobacco. The model is an objective method for providing serum THC concentrations up to 8 h after smoking cannabis with a high THC content (up to 23%).

Jahanfar S; Sharifah H. Effects of restricted caffeine intake by mother on fetal, neonatal and pregnancy outcome. (review). Cochrane Database of Systematic Reviews 2009(2): article CD006965, 2009. (33 refs.)

Background: Maternal caffeine consumption during pregnancy may have adverse effects on fetal, neonatal and maternal outcomes. Objectives This review investigates the effects of restricting caffeine intake by mothers on fetal, neonatal and pregnancy outcomes. Search strategy: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register ( December 2008), scanned bibliographies of published studies and corresponded with investigators. Selection criteria: Randomised controlled trials including quasi-randomised controlled trials (RCTs) investigating the effect of caffeine and/ or supplementary caffeine versus restricted caffeine intake or placebo on pregnancy outcome. Data collection and analysis: The two review authors independently assessed trial quality and extracted data. Main results: One study met the inclusion criteria. Caffeinated instant coffee ( 568 women) was compared with decaffeinated instant coffee ( 629 women) and it was found that reducing the caffeine intake of regular coffee drinkers (3+ cups/day) during the second and third trimester by an average of 182 mg/day did not affect birthweight or length of gestation. Authors' conclusions: There is insufficient evidence to confirm or refute the effectiveness of caffeine avoidance on birthweight or other pregnancy outcomes. There is a need to conduct high-quality, double-blinded RCTs to determine whether caffeine has any effect on pregnancy outcome. PLAIN LANGUAGE SUMMARY: Caffeine is a stimulant found in tea, coffee, cola, chocolate and some over-the-counter medicines. Conflicting results found in the literature make it difficult for health professionals to advise pregnant women about avoiding caffeine during pregnancy. Clearance of caffeine from the mother's blood slows down during pregnancy. Some authors of observational studies have concluded that caffeine intake is harmful to the fetus, causing growth restriction, reduced birthweight, preterm birth or stillbirth. The newborn could also have withdrawal symptoms if the mother has a high intake of caffeine ( more than eight cups of coffee per day). Only one controlled study was identified. The study was based in Denmark. Women less than 20 weeks pregnant were randomly assigned to drinking caffeinated instant coffee ( 568 women after exclusions) or decaffeinated instant coffee ( 629 women). Drinking three cups of coffee a day in early pregnancy had no effect on birthweight, preterm births or growth restriction. Sufficient evidence is not available from randomised controlled trials to support any benefits from avoiding caffeine during pregnancy.

Jain RB; Wang RY. Association of caffeine consumption and smoking status with the serum concentrations of polychlorinated biphenyls, dioxins, and furans in the general U.S. population: NHANES 2003-2004. Journal of Toxicology and Environmental Health. Part A: Current Issues 74(18): 1225-1239, 2011. (36 refs.)

Smoking appears to enhance the body's clearance of dioxins and dioxin-like polychlorinated biphenyls (PCB) by inducing CYP1A2 activity based on studies with a limited number of participants. This hypothesis was evaluated by using data from National Health and Nutrition Examination Survey. Specifically, adult participants were identified and the sums of their serum lipid-adjusted concentrations of 12 polychlorinated dibenzo-p-dioxins/polychlorinated dibenzofurans (PCDD/PCDF) congeners, 33 PCB (total), 26 non-dioxin-like PCB, and 6 mono-ortho (dioxin-like) PCB were determined. In addition to evaluating the association of smoking, the association of caffeine consumption and the interaction between them was evaluated. Data analysis included regression models that were fitted with age, gender, race/ethnicity, and body mass index (BMI). R(2) varied from 34.8 to 66%. Smokers had significantly lower concentrations of total PCDD/PCDF than nonsmokers. New to this study, a siginificant interaction between caffeine consumption and smoking for total PCB was found. When caffeine was consumed less than once a day, smokers had higher concentrations of total PCB than nonsmokers. However, when caffeine was consumed at least once a day, smokers had lower concentrations than nonsmokers. A significant interaction between age and caffeine consumption frequency for each of the PCB groups was also observed. The differences in concentration between younger and older age groups were greater when caffeine was consumed at least once a day than when caffeine was consumed less frequently. Smoking and caffeine consumption need to be considered in the interpretation of human biomonitoring data because they appear to affect the serum concentrations of these chemicals.

Kapur BM; Hutson JR; Chibber T; Luk A; Selby P. Methadone: A review of drug-drug and pathophysiological interactions. (review). Critical Reviews In Clinical Laboratory Sciences 48(4): 171-195, 2011. (236 refs.)

Numerous established and potential drug interactions with methadone are clinically important in people treated with methadone either for addiction or for chronic pain. Methadone users often have comorbidities and are prescribed drugs that may interact with methadone. Methadone is extensively metabolized by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP 1A2, 2D6, 2D8, 2C9/2C8, 2C19, and 2B6. Eighty-six percent of methadone is protein bound, predominately to alpha(1)-acid glycoprotein (AGP). Polymorphisms in or interactions with CYPs that metabolize methadone, changes in protein binding, and other pathophysiological conditions affect the pharmacokinetic properties of methadone. It is critical for health care providers who treat patients on methadone to have adequate information on the interactions of methadone with other drugs of abuse and other medications. We set out to describe drug-drug interactions as well as physiological and pathophysiological factors that may impact the pharmacokinetics of methadone. Using MEDLINE, we conducted a systematic search for papers and related abstracts published between 1966 and June 2010. Keywords that included methadone, drug-drug interactions, CYP P450 and AGP identified a total of 7709 papers. Other databases, including the Cochrane Database of Systematic Reviews and Scopus, were also searched; an additional 929 papers were found. Final selection of 286 publications was based on the relevance of each paper to the topic. Over 50 such interactions were found. Interactions of methadone with other drugs can lead to increased or decreased methadone drug levels in patients and result in potential overdose or withdrawal, respectively. The former can contribute to methadone's fatality. Prescribers of methadone and pharmacists should enquire about any new medications (including natural products and over-the-counter medications) periodically, and especially when an otherwise stable patient suddenly experiences drug craving, withdrawal or intoxication.

Keskitalo-Vuokko K; Pitkaniemi J; Broms U; Heliovaara M; Aromaa A; Perola M et al. Associations of nicotine intake measures with CHRN genes in Finnish smokers. Nicotine & Tobacco Research 13(8): 686-690, 2011. (25 refs.)

Introduction: Genetic effects contribute to individual differences in smoking behavior. Persistence to smoke despite known harmful health effects is mostly driven by nicotine addiction. As the physiological effects of nicotine are mediated by nicotinic acetylcholine receptors (nAChRs), we aimed at examining whether single nucleotide polymorphisms (SNPs) residing in nAChR subunit (CHRN) genes, other than CHRNA3/CHRNA5/ CHRNB4 gene cluster previously showing association in our sample, are associated with smoking quantity or serum cotinine levels. Methods: The study sample consisted of 485 Finnish adult daily smokers (age 30-75 years, 59% men) assessed for the number of cigarettes smoked per day (CPD) and serum cotinine level. We first studied SNPs residing on selected nAChR subunit genes (CHRNA2, CHRNA4, CHRNA6/CHRNB3, CHRNA7, CHRNA9, CHRNA10, CHRNB2, CHRNG/CHRND) genotyped within a genome-wide association study for single SNP and multiple SNP associations by ordinal regression. Next, we explored individual haplotype associations using sliding window technique. Results: At one of the 8 loci studied, CHRNG/CHRND (chr2), single SNP (rs1190452), multiple SNP, and 2-SNP haplotype analyses (SNPs rs4973539-rs1190452) all showed statistically significant association with cotinine level. The median cotinine levels varied between the 2-SNP haplotypes from 220 ng/ml (AA haplotype) to 249 ng/ml (AG haplotype). We did not observe significant associations with CPD. Conclusions: These results provide further evidence that the g-d nAChR subunit gene region is associated with cotinine levels but not with the number of CPD, illustrating the usefulness of biomarkers in genetic analyses.

Kharasch ED; Walker A; Whittington D; Hoffer C; Bedynek PS. Methadone metabolism and clearance are induced by nelfinavir despite inhibition of cytochrome P4503A (CYP3A) activity. Drug and Alcohol Dependence 101(3): 158-168, 2009. (63 refs.)

Background: Methadone plasma concentrations are decreased by nelfinavir. Methadone clearance and the drug interactions have been attributed to CYP3A4, but actual mechanisms of methadone clearance and the nelfinavir interaction are unknown. We assessed nelfinavir effects on methadone pharmacokinetics and pharmacodynamics, intestinal and hepatic CYP3A4/5 activity, and intestinal P-glycoprotein transport activity. CYP3A4/5 and transporters were assessed using alfentanil and fexofenadine, respectively. Methods: Twelve healthy HIV-negative volunteers underwent a sequential crossover. On three consecutive days they received oral alfentanil plus fexofenadine, intravenous alfentanil, and intravenous plus oral methadone. This was repeated after nelfinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were measured by pupil diameter change (miosis). Results: Nelfinavir decreased intravenous and oral methadone plasma concentrations 40-50%. Systemic clearance, hepatic clearance, and hepatic extraction all increased 1.6- and 2-fold, respectively, for R- and S-methadone: apparent oral clearance increased 1.7- and 1.9-fold. Nelfinavir stereoselectively increased (S > R) methadone metabolism and metabolite formation clearance, and methadone renal clearance. Methadone bioavailability and P-glycoprotein activity were minimally affected. Nelfinavir decreased alfentanil systemic and apparent oral clearances 50 and 76%, respectively. Nelfinavir appeared to shift the methadone plasma concentration-effect (miosis) curve leftward and upward. Conclusions: Nelfinavir induced methadone clearance by increasing renal clearance, and more so by stereoselectively increasing hepatic metabolism, extraction and clearance. Induction occurred despite 50% inhibition of hepatic CYP3A4/5 activity and more than 75% inhibition of first-pass CYP3A4/5 activity, suggesting little or no role for CYP3A in clinical methadone disposition. Nelfinavir may alter methadone pharmacodynamics, increasing clinical effects.

Kohler E; Avenarius S; Rabsilber A; Gerloff C; Jorch G. Nicotine and its metabolites in amniotic fluid at birth: Assessment of prenatal tobacco smoke exposure. Human & Experimental Toxicology 29(5): 385-391, 2010. (27 refs.)

Amniotic fluid was collected from 78 pregnant women at birth additionally with their urine prior to delivery as well as neonatal urine and meconium. The smoking markers, nicotine and its metabolites cotinine and trans-3'-hydroxycotinine (OH-cotinine), were determined using high-performance liquid chromatography (HPLC). The self-reported smoking status during pregnancy determined by means of a questionnaire was verified by measurement of maternal urine. In all smokers, nicotine metabolites were detected in amniotic fluid and in 80% of them nicotine as well. However, the sum of the nicotine metabolites (Sum(met)) was significantly lower (p < .001) in amniotic fluid (704 +/- 464 nmol/L) than in meconium (921 +/- 588 nmol/L), neonatal urine (1139 +/- 813 nmol/L) and maternal urine (4496 +/- 3535 nmol/L). Concentrations of nicotine metabolites in amniotic fluid correlated well (p < .001) with that in the other specimen types. After environmental tobacco smoke (ETS) exposure, no nicotine or nicotine metabolites were detectable in amniotic fluid but only in maternal and neonatal urine. Analysis of amniotic fluid at birth lends itself to verifying smoking habits during pregnancy and clearly discriminating from ETS exposure, but it is not a suitable approach to differentiating between ETS exposure and non-exposure.

Kress HG. Clinical update on the pharmacology, efficacy and safety of transdermal buprenorphine. (review). European Journal of Pain 13(3): 219-230, 2009. (109 refs.)

Buprenorphine was not used widely in clinical practice over many years, mainly due to analgesic potency and clinical safety concerns based on misinterpreted animal data. Contrary to previous concerns, however, no analgesic ceiling effect and no antagonism of combined pure p-opioid receptor agonists is seen within the therapeutic dose range. In recent studies, buprenorphine could be effectively and safely combined with full mu-agonists, and switching between buprenorphine and another opioid provided comparable pain relief based on equianalgesic doses. Moreover, buprenorphine exerts an anti hyperalgesic effect, which is due-at least in part-to antagonistic activity at K-opioid receptors. Buprenorphine pharmacokinetics are not altered by advanced age or renal dysfunction. In addition, the risk of respiratory depression is lower than with other opioids including morphine, hydromorphone, methadone and fentanyl. Unlike morphine and fentanyl, there is no immunosuppressive activity with buprenorphine at therapeutic analgesic doses, Transdermal buprenorphine has significantly improved the clinical use of the drug, providing continuous buprenorphine release for Lip to 96 h. In clinical trials, patients receiving transdermal buprenorphine experienced significantly greater pain relief, better sleep, and a reduced need for rescue therapy, compared to placebo. Large-scale post-marketing studies have confirmed the effectiveness of transdermal buprenorphine in treating moderate-to-severe cancer and non-cancer pain including neuropathic syndromes. Finally, the comparably low incidence of CNS adverse events and constipation, and the possibility of use in severe renal dysfunction without a need for dose adjustment make buprenorphine well suited for chronic pain management in at-risk patients, such as diabetics, elderly or renally impaired individuals including those requiring haemodialysis.

Lerman C; Jepson C; Wileyto EP; Patterson F; Schnoll R; Mroziewicz M et al. Genetic variation in nicotine metabolism predicts the efficacy of extended-duration transdermal nicotine therapy. Clinical Pharmacology and Therapeutics 87(5): 553-557, 2010. (23 refs.)

In a placebo-controlled trial, we examined the efficacy of a 6-month ("extended") transdermal nicotine therapy vs. the 8-week ("standard") therapy in 471 Caucasian smokers with either normal or reduced rates of nicotine metabolism as determined at pretreatment. Extended therapy was superior to standard therapy in genotypic or phenotypic reduced metabolizers (RMs) of nicotine but not in normal metabolizers (NMs). RMs of nicotine are candidates for extended transdermal nicotine therapy, whereas an alternative therapeutic approach may be needed for those with normal rates of nicotine metabolism.

Lessov-Schlaggar CN; Benowitz NL; Jacob P; Swan GE. Genetic influences on individual differences in nicotine glucuronidation. Twin Research and Human Genetics 12(5): 507-513, 2009. (19 refs.)

Nicotine and its primary oxidative metabolites are metabolized in part by glucuronidation. Genetic variation in UGT isoenzymes that catalyze glucuronidation activity suggests that variation in glucuronidation rate is in part genetically determined. The relative contribution of genetic and environmental sources to individual differences in the rate of glucuronidation of nicotine, cotinine, and trans-3'-hydroxycotinine was estimated in a twin study of nicotine pharmacokinetics. Glucuronidation rate was defined using measures that either accounted for variability in renal clearance or assumed the same relative renal clearance of parent drug and glucuronide conjugate across individuals. The former definition resulted in highly correlated nicotine and cotinine glucuronidation measures that were substantially influenced by the combined effect of additive (heritable) and non-additive (dominant and epistatic) genetic effects. These findings suggest that genetic variation in UGT isoenzymes that act in additive and interactive ways is an important determinant of individual variability in nicotine and cotinine metabolism via glucuronidation pathways.

Li LH; Everhart T; Jacob P; Jones R; Mendelson J. Stereoselectivity in the human metabolism of methamphetamine. British Journal of Clinical Pharmacology 69(2): 187-192, 2010. (17 refs.)

AIM: To characterize the formation and urinary elimination of metabolites of S-(+) and R-(-) methamphetamine (MA) in humans. METHODS: In this 12-subject, six-session, double-blind, placebo-controlled, balanced, crossover design study, the formation of the MA metabolites para hydroxymethamphetamine (pOH-MA) and amphetamine (AMP) were determined in urine after intravenous doses of S-(+)-MA 0.25 and 0.5 mg kg(-1), R-(-)-MA 0.25 and 0.5 mg kg(-1), racemic MA 0.5 mg kg(-1), or placebo. Parent drug and metabolite levels in urine and plasma were measured by gas chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by noncompartmental models using WinNonlin. RESULTS: An approximately threefold enantioselectivity difference in elimination was observed for AMP, with 7% of the dose converted to S-(+)-AMP vs. 2% to R-(-)-AMP (P < 0.001). Furthermore, less R-(-)-pOH-MA was excreted in the urine compared with S-(+)-pOH-MA (8% vs. 11%, P = 0.02). Correspondingly, S-(+)-MA excretion was less than R-(-)-MA (42% vs. 52%; P = 0.005). CONCLUSIONS: The metabolism of MA is enantioselective, with formation of AMP having the highest isomer selectivity. A greater percentage of MA is converted to pOH-MA (8-11%) than AMP (2-7%). The formation of pOH-MA was less affected by the MA enantiomer administered, suggesting that urine pOH-MA may be a more stable biomarker of MA metabolism.

Li LH; Galloway GP; Verotta D; Everhart ET; Baggott MJ; Coyle JR; Lopez JC; Mendelson J. A method to quantify illicit intake of drugs from urine: Methamphetamine. Journal of Pharmacology and Experimental Therapeutics 338(1): 31-36, 2011. (16 refs.)

Qualitative urinalysis can verify abstinence of drug misuse but cannot detect changes in drug intake. For drugs with slow elimination, such as methamphetamine (MA), a single episode of abuse can result in up to 5 days of positive urine drug screens. Thus, interventions that produce substantial decreases in drug use but do not achieve almost complete abstinence are classified as ineffective. Using nonpharmacologic doses of deuterium-labeled /-methamphetamine (/-MA-d(3)) we have developed a simple, robust method that reliably estimates changes in MA intake. Twelve subjects were dosed with 5 mg of /-MA-d(3) daily and challenged with 15, 30, and 45 mg of nonlabeled d-MA (d-MA-d(0)) after reaching plasma steady status of /-MA-d(3). Urinary concentration ratios of d-MA-d(0) to l-MA-d(3) provided clear separation of the administered doses with as little as 15-mg dose increments. Administered doses could not be resolved using d-MA-d(0) concentrations alone. In conclusion, the urinary [d-MA-d(0)]:[/-MA-d(3)] provides a quantitative, continuous measure of illicit MA exposure. The method reliably detects small, clinically relevant changes in illicit MA intake from random urine specimens, is amenable to deployment in clinical trials, and can be used to quantify patterns of MA abuse.

Lowe RH; Abraham TT; Darwin WD; Herning R; Cadet JL; Huestis MA. Extended urinary Delta 9-tetrahydrocannabinol excretion in chronic cannabis users precludes use as a biomarker of new drug exposure. Drug and Alcohol Dependence 105(1/2): 24-32, 2009. (30 refs.)

Background: Generally, urinary 11-nor-9-carboxy-Delta 9-tetrahydrocannabinol (THCCOOH) after alkaline hydrolysis is monitored to detect cannabis exposure, although last use may have been weeks prior in chronic cannabis users. Delta 9-Tetrahydrocannabinol (THC) and 11-hydroxy-THC (11-OH-THC) concentrations in urine following Escherichia coli (beta-glucuronidase hydrolysis were proposed as biomarkers of recent (within 8 h) cannabis use. Objective: To test the validity of THC and 11-OH-THC in urine as indicators of recent cannabis use. Methods: Monitor urinary cannabinoid excretion in 33 chronic cannabis smokers who resided on a secure research unit under 24 h continuous medical surveillance. All urine specimens were collected individually ad libidum for up to 30 days, were hydrolyzed with a tandem E. coli beta-glucuronidase/base procedure, and analyzed for THC, 11-OH-THC and THCCOOH by one-and two-dimensional-cryotrap gas chromatography mass spectrometry (2D-GCMS) with limits of quantification of 2.5 ng/mL. Results: Extended excretion of THC and 11-OH-THC in chronic cannabis users' urine was observed during monitored abstinence; 14 of 33 participants had measurable THC in specimens collected at least 24 h after abstinence initiation. Seven subjects had measurable THC in urine for 3, 3, 4, 7, 7, 12, and 24 days after cannabis cessation. 11-OH-THC and THCCOOH were detectable in urine specimens from one heavy, chronic cannabis user for at least 24 days. Conclusion: For the first time, extended urinary excretion of THC and 11-OH-THC is documented for at least 24 days, negating their effectiveness as biomarkers of recent cannabis exposure, and substantiating long terminal elimination times for urinary cannabinoids following chronic cannabis smoking.

Marchei E; Farre M; Pardo R; Garcia-Algar O; Pellegrini M; Pacifici R et al. Usefulness of sweat testing for the detection of methylphenidate after fast- and extended-release drug administration: A pilot study18. Therapeutic Drug Monitoring 32(4): 508-511, 2010. (18 refs.)

The pharmacokinetics of methylphenidate (MPH), a prescription amphetamine derivative used in the treatment of attention-deficit hyperactivity disorder, has been amply described in conventional biological matrices. Recently, the excretion of MPH and its principal metabolite, ritalinic acid (RA) in oral fluid and plasma after a single drug administration has been described. The aim of this study was to describe the excretion of MPH and RA in sweat after the administration of a single dose of either fast-release or extended-release MPH. Three male subjects received 2 simultaneous oral doses of 10 mg fast-release MPH, and 1 male subject received one dose of 20 mg extended-release MPH. Sweat patches were applied to the back of each participant and removed at timed intervals. MPH and RA were determined in patches using a previously validated liquid chromatography-electrospray ionization mass spectrometric method. MPH was detected in sweat after the administration of fast-and extended-release formulations. For the fast-release formulation, MPH appeared in the sweat patches 2 hours after administration with a maximum of 15.9 nanogram per patch, reached after 24 hours. Mean total MPH excreted was 0.02 mg (about 0.08% of the administered dose). For the extended-release formulation, MPH appeared in the sweat 5 hours after administration and reached a maximum of 34.3 nanogram per patch after 24 hours. Mean total MPH excreted was 0.04 mg (about 0.18% of the administered dose). RA was not detected in either of the sweat patches probably because of its acidic properties. Measuring MPH in sweat patches can be a viable alternative to urine testing for noninvasive monitoring of use and misuse of the drug.

Maurer HH. Chemistry, pharmacology, and metabolism of emerging drugs of abuse. (review). Therapeutic Drug Monitoring 32(5): 544-549, 2010. (94 refs.)

In recent years, besides the classic designer drugs of the amphetamine type, a series of new drug classes appeared on the illicit drugs market. The chemistry, pharmacology, toxicology, metabolism, and toxicokinetics is discussed of 2,5-dimethoxy amphetamines, 2,5-dimethoxy phenethylamines, beta-keto-amphetamines, phencyclidine derivatives as well as of herbal drugs, ie, Kratom. They have gained popularity and notoriety as rave drugs. The metabolic pathways, the involvement of cytochrome P450 isoenzymes in the main pathways, and their roles in hepatic clearance are also summarized.

McCance-Katz EF; Jatlow P; Rainey PM. Effect of cocaine use on methadone pharmacokinetics in humans. American Journal on Addictions 19(1): 47-52, 2010. (33 refs.)

Chronic cocaine use has been shown to significantly decrease buprenorphine concentrations in the blood with potential for adverse events and poor treatment response. In this study, we investigated whether a similar drug interaction occurred between cocaine and methadone. In a retrospective analysis, methadone pharmacokinetics were compared for those who were either regular cocaine users (N = 16) or with intermittent or no cocaine use (N = 23). Participants who used cocaine regularly showed a significant decrease in C-min (p = .04) and a trend for decreased AUC (p = .09) and more rapid methadone clearance (p = .08). Regular cocaine use may adversely impact treatment outcomes for opioid dependence in those receiving methadone maintenance by decreasing methadone exposure.

Meyer MR; Maurer HH. Absorption, distribution, metabolism and excretion pharmacogenomics of drugs of abuse. (review). Pharmacogenomics 12(2): 215-233, 2011. (220 refs.)

Pharmacologic and toxic effects of xenobiotics, such as drugs of abuse, depend on the genotype and phenotype of an individual, and conversely on the isoenzymes involved in their metabolism and transport. The current knowledge of such isoenzymes of frequently abused therapeutics such as opioids (oxycodone, hydrocodone, methadone, fentanyl, buprenorphine, tramadol, heroin, morphine and codeine), anesthetics (y-hydroxybutyric acid, propofol, ketamine and phencyclidine) and cognitive enhancers (methylphenidate and modafinil), and some important plant-derived hallucinogens (lysergide, salvinorin A, psilocybin and psilocin), as well as of nicotine in humans are summarized in this article. The isoenzymes (e.g., cytochrome P450, glucuronyltransferases, esterases and reductases) involved in the metabolism of drugs and some pharmacokinetic data are discussed. The relevance of such data is discussed for predicting possible interactions with other xenobiotics, understanding pharmacokinetic behavior and pharmacogenomic variations, assessing toxic risks,

Meyer MR; Maurer HH. Metabolism of designer drugs of abuse: An updated review. (review). Current Drug Metabolism 11(5): 468-482, 2010. (135 refs.)

This paper reviews the metabolism of new designer drugs of abuse that have emerged on the black market during the last years and is an update of a review published in 2005. The presented review contains data concerning the so-called 2C compounds (phenethylamine type) such as 4-bromo-2,5-dimethoxy-beta-phenethylamine (2C-B), 4-iodo-2,5-dimethoxy-beta-phenethylamine (2C-I), 2,5-dimethoxy-4-methyl-beta-phenethylamine (2C-D), 4-ethyl-2,5-dimethoxy-beta-phenethylamine (2C-E), 4-ethylthio-2,5-dimethoxy-betaphenethylamine (2C-T-2), and 2,5-dimethoxy-4-propylthio-beta-phenethylamine (2C-T-7), beta-keto designer drugs such as 2-methylamino-1-(3,4-methylenedioxyphenyl)butan-1-one (butylone, bk-MBDB), 2-ethylamino-1-(3,4-methylenedioxyphenyl)propan-1one (ethylone, bk-MDEA), 2-methylamino-1-(3,4-methylenedioxyphenyl)propan-1-one (methylone, bk-MDMA), and 2-methylamino-1-p-tolylpropane-1-one (mephedrone, 4-methyl-methcathinone), pyrrolidinophenones such as 4-methyl-pyrrolidinobutyrophenone (MPBP) and alpha-pyrrolidinovalerophenone (PVP), phencyclidine-derived drugs such as N-(1-phenylcyclohexyl)-propanamine (PCPr), N-(1-phenyl-cyclohexyl)-2-ethoxyethanamine (PCEEA), N-(1-phenylcyclohexyl)-3-methoxypropanamine (PCMPA), and N-(1-phenylcyclohexyl)-2-methoxyethanamine (PCMEA), tryptamines such as 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT), and finally alpha-methylfentanyl (alpha-MF) and 3-methylfentanyl (3-MF). Papers have been considered and reviewed on the identification of in vivo or in vitro human or animal metabolites and the cytochrome P450 or monoamineoxidase isoenzyme-dependent metabolism.

Meyer MR; Wilhelm J; Peters FT; Maurer HH. Beta-keto amphetamines: Studies on the metabolism of the designer drug mephedrone and toxicological detection of mephedrone, butylone, and methylone in urine using gas chromatography-mass spectrometry. Analytical and Bioanalytical Chemistry 397(3): 1225-1233, 2011. (25 refs.)

In recent years, a new class of designer drugs has appeared on the drugs of abuse market in many countries, namely, the so-called beta-keto (bk) designer drugs such as mephedrone (bk-4-methylmethamphetamine), butylone (bk-MBDB), and methylone (bk-MDMA). The aim of the present study was to identify the metabolites of mephedrone in rat and human urine using GC-MS techniques and to include mephedrone, butylone, and methylone within the authors' systematic toxicological analysis (STA) procedure. Six phase I metabolites of mephedrone were detected in rat urine and seven in human urine suggesting the following metabolic steps: N-demethylation to the primary amine, reduction of the keto moiety to the respective alcohol, and oxidation of the tolyl moiety to the corresponding alcohols and carboxylic acid. The STA procedure allowed the detection of mephedrone, butylone, methylone, and their metabolites in urine of rats treated with doses corresponding to those reported for abuse of amphetamines. Besides macro-based data evaluation, an automated evaluation using the automated mass spectral deconvolution and identification system was performed. Mephedrone and butylone could be detected also in human urine samples submitted for drug testing. Assuming similar kinetics in humans, the described STA procedure should be suitable for proof of an intake of the bk-designer drugs in human urine.

Mitchell SC; Smith RL; Waring RH. The menstrual cycle and drug metabolism. (review). Current Drug Metabolism 10(5): 499-507, 2009. (135 refs.)

Within the field of drug metabolism, when addressing quantitative aspects, an average value is traditionally quoted, commonly the arithmetic mean with perhaps an indication of spread. Better still a range of values may be given, thereby acknowledging that various factors may precipitate differences between individuals. A single subject, however, usually only merits a single value. Nevertheless, events such as an acute illness or concurrent drug therapy serve to alert that this value may change substantially over a relatively short time-period, although any potential effects of naturally occurring phenomena, such as the female menstrual cycle, are often overlooked or disregarded. Are the biochemical and physiological changes that occur during the menstrual cycle able to influence xenobiotic metabolism? Is the idea of a stable and unwavering baseline within a single healthy individual flawed? Is it time to reassess our thinking with regards to such aspects? This brief review explores these issues and examines information available within the literature for evidence of potential influences of menstrual cycle events upon drug metabolism, defined as the actual chemical alteration of the parent molecule into another chemical species.

Moody DE; Fang WFB; Morrison J; McCance-Katz E. Gender differences in pharmacokinetics of maintenance dosed buprenorphine. Drug and Alcohol Dependence 118(2-3): 479-483, 2011. (40 refs.)

Aims: Gender differences are known to occur in the pharmacokinetics of many drugs. Mechanisms may include differences in body composition, body weight, cardiac output, hormonal status, and use of different co-medications. Recently subtle gender-dependent differences in cytochrome P450 (CYP) 3A-dependent metabolism have been demonstrated. Buprenorphine N-dealkylation to norbuprenorphine is primarily performed by CYP3A. We therefore asked whether gender-dependent differences occur in the pharmacokinetics of buprenorphine. Methods: A retrospective examination was made of control (buprenorphine/naloxone-only) sessions from a number of drug interaction studies between buprenorphine and antiretroviral drugs. Twenty males and eleven females were identified who had a negative cocaine urine test prior to participation in the control session and were all on the same maintenance dose (16/4 mg) of sublingual buprenorphine/naloxone. Pharmacokinetic data from their control sessions (buprenorphine/naloxone only) were sorted by gender and compared using the two-sample t-test. Results: Females had significantly higher area under the plasma concentration curve (AUC) and maximum plasma concentrations for buprenorphine, norbuprenorphine and norbuprenorphine-3-glucuronide. AUCs relative to dose per body weight and surface area were significantly higher for only norbuprenorphine. AUCs relative to lean body mass were, however, not significantly different. Conclusions: Gender-related differences exist in the pharmacokinetics of buprenorphine; differences in body composition appear to have a major impact; differences in CYPA-dependent metabolism may also contribute.

Moolchan ET; Parzynski CS; Jaszyna-Gasior M; Collins CC; Leff MK; Zimmerman DL. A link between adolescent nicotine metabolism and smoking topography. Cancer Epidemiology, Biomarkers & Prevention 18(5): 1578-1583, 2009. (29 refs.)

Adult slow nicotine metabolizers have lower smoke exposure, carbon monoxide levels, and plasma nicotine levels than normal and fast metabolizers. Emerging evidence suggests nicotine metabolism influences smoking topography. This study investigated the association of nicotine metabolism (the ratio of plasma 3-hydroxycotinine to cotinine; 3OHCOT/COT) with smoking topography in adolescent smokers (n = 85; 65% female, 68% European American; mean age, 15.3 +/- 1.2 years; mean cigarettes per day, 18.5 +/- 8.5; mean Fagerstrom Test for Nicotine Dependence, 7.0 +/- 1.2) presenting for a nicotine replacement therapy trial. Measures obtained included puff volume, interpuff interval, number of puffs, puff duration, and puff velocity. Linear regression analysis controlling for hormonal contraception use showed that 30HCOT/COT ratios predicted mean puff volume in the overall sample (t = 2.126; P = 0.037; adjusted R-2 = 0.067). After gender stratification, faster metabolism predicted higher mean puff volume (t = 2.81; P = 0.009; adjusted R-2 = 0.192) but fewer puffs (t = -3.160; P = 0.004; adjusted R-2 = 0.237) and lower mean puff duration (t = -2.06; P = 0.048; adjusted R-2 = 0.101) among boys only, suggesting that as nicotine metabolism increases, puff volume increases but puffing frequency decreases. No significant relationships were found between nicotine metabolism and total puff volume, mean puff duration, interpuff interval, or puff velocity. If confirmed in a broader sample of adolescent smokers, these findings suggest that as among dependent adult smokers, rate of metabolism among adolescent boys is linked to select parameters of puffing behavior that may affect cessation ability.

Oechsler S; Skopp G. Buprenorphine and major metabolites in blood specimens collected for drug analysis in law enforcement purposes. Forensic Science International 195(1-3): 73-77, 2010. (22 refs.)

A liquid chromatographic/electrospray ionization tandem mass spectrometric method for the quantification of buprenorphine (BUP), norbuprenorphine (NBUP), buprenorphine-3-beta-D-glucuronide (BUPG) and norbuprenorphine-3-beta-D-glucuronide (NBUPG) in serum samples was developed and validated. Pre-treatment of BUP and NBUP was by liquid-liquid extraction, while glucuronides were favourably isolated by solid phase extraction. Separation in 2 separate runs (2 x 5 min) was achieved using isocratic elution. The method was applied to 20 authentic serum specimens collected for law enforcement purposes where BUP intake had been indicated. The parent drug was not detectable in half of the specimens at a lower limit of detection of 0.2 ng/mL, whereas NBUP could be determined from any sample but one. NBUPG is the majormetabolite present, which could be identified along with BUPG in all samples under investigation. In authentic specimens it could be advisable to monitor BUP metabolites along with the parent drug.

Quaak M; van Schayck CP; Knaapen AM; van Schooten FJ. Implications of gene-drug interactions in smoking cessation for improving the prevention of chronic degenerative diseases. (review). Mutation Research 667(1-2, Special Issue): 44-57, 2009. (137 refs.)

Tobacco smoking continues to be the major preventable cause of premature morbidity and mortality throughout the world. Recent research strongly suggests that genetic background is associated with several aspects of smoking (e.g. initiation, maintenance, cessation, number of cigarettes smoked, indicators of nicotine dependence (ND) and nicotine withdrawal). Variations in two broad classes of genes have been shown to influence smoking: (1) genes that may influence the response to nicotine (e.g. nicotine metabolism, nicotinic receptors) and (2) genes that may predispose to addictive behaviour via their effects on key neurotransmitter pathways (e.g. dopamine, serotonin and opioid). Since these genetic variants might also influence the response to smoking cessation pharmacotherapies, smoking cessation rates might be increased by determining which treatment would be most effective based on the smoker's genetic background. This is expected to result in a more efficient use of smoking cessation therapies, increased cessation rates and ultimately, in reduced deaths from smoking. Until now, most research on the influence of genetic variation on smoking cessation pharmacotherapy has been directed to the two most widely accepted and licensed forms of smoking cessation therapy: nicotine replacement therapy (NRT) and the antidepressant bupropion. overall, genotypes associated with increased dopamine availability seem to predict a better response to bupropion, while smokers with genotypes associated with reduced dopamine levels probably achieve better quit rates with NRT. A decreased metabolism for the drug used (e.g. bupropion or NRT), results in increased cessation rates as well. Furthermore, smokers with reduced dopaminergic and nicotinic receptor activity variants may experience greater benefit from nicotine spray, while smokers with increased activity variants in the opioid receptor may have greater success with transdermal patches. Thus it seems that genetic information may give directions in determining which treatment would be most effective for an individual smoker. However, several challenges will still have to be overcome before genetically tailored smoking cessation therapy can be implemented in standard clinical practice.

Perez-Stable EJ; Benowitz NL. Do biological differences help explain tobacco-related disparities? (commentary). American Journal of Health Promotion 25(5, Supplement S): s8-s10, 2011. (27 refs.)

This commentary notes that smoking behaviors vary by age, eductional level, economic status, gender/race/ethnicity and geographical education. Epidemiology studies have identified higher rates of smoking among men, whites, and AfricanAmericans, and those with less than high school education among nonimmigrants. Immigrants from Latin America and Asia tend to have lower rates of smoking, especially among women. In addition, nondaily smoking or smoking 5 or fewer cigarettes per day is more common among nonwhite smokers. This commentary raises questions about a possible genetic basis for these differences. Racial differences in nicotine metabolism have been identified. For example, AfricanAmericans metabolize and eliminate nicotine more slowly and inhale higher doses of nicotine per cigarette. Latinos of Mexican and Central American national origin metabolize nicotine at the same rate as whites and have a similar intake of nicotine. ChineseAmerican metabolize and clear nicotine more slowly and absorb less nicotine per cigareete. There is a brief review of other biological differences identified, in terms of cotinine levels. Also there are significant differnences in exposure to secondhand smoke and differences in serum cotinine levels of nonsmokers. Other questions raised are whether nicotine differences in metabolism affect cessation, and also genetic factors related to lung cancer.

Reddick AD; Hodge K; Morrison WG. Effect of concomitant opiate ingestion on paracetamol levels in acute overdose. Emergency Medicine Journal 27(10): 742-744, 2010 , 2010. (11 refs.)

Aim: To assess whether the co-ingestion of opiates in acute paracetamol overdose has an effect on the paracetamol level 4 h after ingestion. Methods: A prospective observational study was performed in the emergency department of a teaching hospital. The paracetamol levels at 4 h of consecutive patients who had taken an overdose of either paracetamol alone or in conjunction with an opiate were collected over a 4-month period. The data were then analysed. Results: After exclusions, the results of 21 patients who took paracetamol alone and 20 who took paracetamol and an opiate showed that paracetamol levels were significantly lower at 4 h if there was co-ingestion of an opiate. Analysis shows that opiate ingestion is a predictor for paracetamol levels at 4 h. Conclusion: Co-ingestion of opiate decreases the serum paracetamol level at 4 h. If opiate and paracetamol are taken together, there is a case for a repeat measurement of the paracetamol level if the level at 4 h is lower than would be expected in selected patients.

Roberts DM; Smith MWH; Gopalakrishnan M; Whittaker G; Day RO. Extreme gamma-butyrolactone overdose with severe metabolic acidosis requiring hemodialysis. Annals of Emergency Medicine 58(1): 83-85, 2011. (14 refs.)

gamma-Hydroxybutyrate (GHB) and its precursor gamma-butyrolactone (GBL) are commonly abused drugs with a narrow therapeutic index. Therefore, overdoses occur readily with recreational use, and severe poisoning can occur after deliberate self-poisoning. We report the sequelae in a patient who ingested a massive dose of GBL, with suicidal intent. Severe metabolic acidosis and an asystolic cardiac arrest were successfully treated with standard resuscitation, supportive care, and continuous venovenous hemodiafiltration. Plasma GHB concentrations were the highest reported to date. The acidosis was attributed to rapid systemic absorption of GBL, followed by rapid metabolism to GHB.

Rodeiro I; Donato MT; Jimenez N; Garrido G; Molina-Torres J; Menendez R et al. Inhibition of Human P450 Enzymes by natural extracts used in traditional medicine. Phytotherapy Research 23(2): 279-282, 2009. (21 refs.)

Different medicinal plants are widely used in Cuba and Mexico to treat several disorders. This paper reports in vitro inhibitory effects on the P450 system of herbal products commonly used by people in Cuba and Mexico in traditional medicine for decades. Experiments were conducted in human liver microsomes. The catalytic activities of CYPIA1/2, 2136, and 3A4 were measured using specific probe substrates. The Heliopsis longipes extract exhibited a concentration-dependent inhibition of the three enzymes, and similar effects were produced by affinin (an alkamide isolated from the H. longipes extract) and two catalytically reduced alkamides. Mangifera indica L. and Thalassia testudinum extracts, two natural polyphenol-rich extracts, diminished CYPIA1/2 and 3A4 activities, but not the CYP2D6 activity. These results suggest that these herbs inhibit the major human P450 enzymes involved in drug metabolism and could induce potential herbal-drug interactions.

Rose ME; Grant JE. Alcohol-induced blackout phenomenology, biological basis, and gender differences. (review). Journal of Addiction Medicine 4(2): 61-73, 2010. (149 refs.)

Blackouts from acute alcohol ingestion are defined as the inability to recall events that occurred during a drinking episode and are highly prevalent in both alcoholic and nonalcoholic populations. This article reviews the clinical manifestations, epidemiology, risk factors, cognitive impairment, and neurobiology associated with alcohol-induced blackout, with special emphasis on the neurochemical and neurophysiological basis, and gender differences. Two types of blackout have been identified: en bloc, or complete inability to recall events during a time period, and fragmentary, where memory loss is incomplete. The rapidity of rise in blood alcohol concentration is the most robust predictor of blackout. Alcohol impairs different brain functions at different rates, and cognitive and memory performance are differentially impaired by ascending versus descending blood alcohol concentration. Cognitive and memory impairment occurs before motor impairment, possibly explaining how a drinker appearing fully functional can have little subsequent memory. Blackouts are caused by breakdown in the transfer of short-term memory into long-term storage and subsequent retrieval primarily through dose-dependent disruption of hippocampal CA1 pyramidal cell activity. The exact mechanism is believed to involve potentiation of gamma-aminobutyric acid-alpha-mediated inhibition and interference with excitatory hippocampal N-methyl-D-aspartate receptor activation, resulting in decreased long-term potentiation. Another possible mechanism involves disrupted septohippocampal theta rhythm activity because of enhanced medial septal area gamma-aminobutyric acid-ergic neurotransmission. Women are more susceptible to blackouts and undergo a slower recovery from cognitive impairment than men, due in part to the effect of gender differences in pharmacokinetics and body composition on alcohol bioavailability.

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; Wileyto EP; Tyndale RF; Benowitz N; Lerman C. Nicotine metabolic rate predicts successful smoking cessation with transdermal nicotine: A validation study. Pharmacology, Biochemistry and Behavior 92(1): 6-11, 2009. (28 refs.)

Transdermal nicotine is widely used for smoking cessation, but only similar to 20% of smokers quit successfully with this medication. Interindividual variability in nicotine metabolism rate may influence treatment response. This study sought to validate, and extend in a larger sample, our previous finding that the ratio of plasma nicotine metabolites 3'-hydroxycotinine (3-HC)/cotinine, a measure of nicotine metabolism rate, predicts response to nicotine patch. A sample of 568 smokers was enrolled in a study that provided counseling and 8-weeks of 21 mg nicotine patch. Pretreatment 3-HC/cotinine ratio was examined as a predictor of 7-day point prevalence abstinence, verified with breath carbon monoxide (CO), 8 weeks after the quit date. Controlling for sex, race, age, and nicotine dependence, smokers in the upper 3 quartiles of 3-HC/cotinine ratio (faster metabolizers) were similar to 50% less likely to be abstinent vs. smokers in the first quartile (slow metabolizers; 28% vs. 42%; OR = .54 [95% CI : .36-.82], p = .003). Among abstainers, plasma nicotine levels (assessed I week after treatment began) decreased linearly across the 3-HC/cotinine ratio (beta = -3.38, t[355] = -3.09, p < .05). These data support the value of the 3-HC/cotinine ratio as a biomarker to predict success with transdermal nicotine for smoking cessation.

Schwaninger AE; Meyer MR; Barnes AJ; Kolbrich-Spargo EA; Gorelick DA; Goodwin RS et al. Stereoselective urinary MDMA (ecstasy) and metabolites excretion kinetics following controlled MDMA administration to humans. Biochemical Pharmacology 83(1): 131-138, 2012. (36 refs.)

The R- and S-enantiomers of racemic 3,4-methylenedioxymethamphetamine (MDMA) exhibit different dose-concentration curves. In plasma, S-MDMA was eliminated at a higher rate, most likely due to stereoselective metabolism. Similar data were shown in various in vitro experiments. The aim of the present study was the in vivo investigation of stereoselective elimination of MDMA's phase I and phase II metabolites in human urine following controlled oral MDMA administration. Urine samples from 10 participants receiving 1.0 and 1.6 mg/kg MDMA separated by at least one week were analyzed blind by liquid chromatography-high resolution-mass spectrometry and gas chromatography-mass spectrometry after chiral derivatization with S-heptafluorobutyrylprolyl chloride. R/S ratios at C(max) were comparable after low and high doses with ratios >1 for MDMA, free DHMA, and HMMA sulfate, and with ratios <1 for MDA, free HMMA, DHMA sulfate and HMMA glucuronide. In the five days after the high MDMA dose, a median of 21% of all evaluated compounds were excreted as R-stereoisomers and 17% as S-stereoisomers. Significantly greater MDMA, DHMA, and HMMA sulfate R-enantiomers and HMMA and HMMA glucuronide S-stereoisomers were excreted. No significant differences were observed for MDA and DHMA sulfate stereoisomers. Changes in R/S ratios could be observed over time for all analytes, with steady increases in the first 48 h. R/S ratios could help to roughly estimate time of MDMA ingestion and therefore, improve interpretation of MDMA and metabolite urinary concentrations in clinical and forensic toxicology.

Shiran MR; Lennard MS; Iqbal MZ; Lagundoye O; Seivewright N; Tucker GT et al. Contribution of the activities of CYP3A, CYP2D6, CYP1A2 and other potential covariates to the disposition of methadone in patients undergoing methadone maintenance treatment. British Journal of Clinical Pharmacology 67(1): 29-37, 2009. (73 refs.)

What is already known about this subject. Several cytochromes P450 (CYPs) have been implicated in the metabolism of methadone, but there is no consensus on their relative contributions to overall disposition and hence variability in response. What this study adds. Variability in CYP3A4 activity has statistically significant but nonetheless modest influence on the oral clearance of methadone and its enantiomers. center dot However, CYPs 1A2 and 2D6 appear to have no impact at all. To investigate the influence of different cytochrome P450 (CYP) activities and other potential covariates on the disposition of methadone in patients on methadone maintenance therapy (MMT). Eighty-eight patients (58 male; 21-55 years; 84 White) on MMT were studied. CYP2D6 activity [3 h plasma metabolic ratio of dextromethorphan (DEX) to dextrorphan (DOR)] was determined in 44 patients (29 male; 24-55 years), CYP1A2 activity (salivary caffeine elimination half-life) in 44 patients (21 male; 24-55 years) and CYP3A activity (oral clearance of midazolam) in 49 patients (33 male; 23-55 years). Data on all three CYPs were obtained from 32 subjects. Total plasma concentrations of (RS)-methadone and total and unbound plasma concentrations of both enantiomers were measured by LC/MS. Population pharmacokinetics and subsequent multiple regression analysis were used to calculate methadone oral clearance and to identify its covariates. Between 61 and 68% of the overall variation in total plasma trough concentrations of (RS)-, (R)- and (S)-methadone was explained by methadone dose, duration of addiction before starting MMT, CYP3A activity and illicit morphine use. CYP3A activity explained 22, 16, 15 and 23% of the variation in unbound (R)-, unbound (S)-, total (RS)- and total (S)-methadone clearances, respectively. Neither CYP2D6 nor CYP1A2 activity was related to methadone disposition. CYP3A activity has a modest influence on methadone disposition. Inhibitors and inducers of this enzyme should be monitored in patients taking methadone.

Signorello LB; Cai QY; Tarone RE; McLaughlin JK; Blot WJ. Racial differences in serum cotinine levels of smokers. Disease Markers 27(5): 187-192, 2009. (31 refs.)

The purpose of this study was to estimate black/white differences in cotinine levels for current smokers of both sexes, and to explore the potential contribution of mentholated cigarettes to these differences. Sera from 255 current smokers sampled from Southern Community Cohort Study participants (65 black men, 65 black women, 63 white men, 62 white women) were analyzed for cotinine, and linear regression was used to model the effect of race on cotinine level, adjusting for the number of cigarettes smoked within the last 24 hours, use of menthol vs. non-menthol cigarettes, exposure to environmental tobacco smoke, and age. Black smokers smoked fewer cigarettes than white smokers, yet had crude mean cotinine levels nearly as high or higher than white smokers. After multivariate adjustment, cotinine levels were an average of 50 ng/ml higher among black than white women (p = 0.008) and non-significantly 12 ng/ml higher among black than white men (p = 0.52). We observed no increase in cotinine levels associated with menthol cigarette use. We conclude that differences in cotinine levels among smokers suggest racial variation in exposure to and/or metabolism of tobacco smoke constituents, but our findings do not support a role for menthol preference in this disparity.

Smith HS. The metabolism of opioid agents and the clinical impact of their active metabolites. (review). Clinical Journal of Pain 27(9): 824-838, 2011. (190 refs.)

Background: The metabolism of opioids is critical to consider for multiple reasons. The most commonly prescribed opioid agents often have metabolites that are active and are the source of both analgesic activity and an increased incidence of adverse events. Many opioids are metabolized by cytochrome P450 enzymes. Polymorphisms in cytochrome P450 genes and inhibition or induction of cytochrome P450 enzymes by coadministered drugs may significantly impact the systemic concentration of opioids and their metabolites and the associated efficacy or adverse events. Methods: This is a narrative review of the metabolism of various opioids that will highlight the impact of their active metabolites, and the potential impact of cytochrome P450 activity on analgesic activity. Results: An understanding of "opioid metabolic machinery," cytochrome P450 activity, and drug-drug interactions in the context of opioid selection may benefit clinicians and patients alike. Conclusions: A greater appreciation of the metabolism of commonly prescribed opioid analgesics and the impact of their active metabolites on efficacy and safety may aid prescribers in tailoring care for optimal outcomes.

Swan GE; Lessov-Schlaggar CN. Tobacco addiction and pharmacogenetics of nicotine metabolism. Journal of Neurogenetics 23(3): 262-271, 2009. (74 refs.)

This paper presents a brief overview of several components of tobacco addiction, including: 1) the epidemiology of smoking in the United States and elsewhere around the world; 2) implications of the pharmacogenetic study of nicotine metabolism for understanding tobacco addiction and its treatment; 3) the use of the twin design as an example of one strategy to understand the contribution of genetic and environmental factors to the pharmacokinetics of nicotine metabolism; 4) results from recent genomic studies of tobacco addiction in adults; and 5) a discussion of progress (past and future) toward the development of a comprehensive understanding of the pharmacogenetics of tobacco addiction and its treatment.

Trathen B; Paterson S; Cordero R; Luty J. Validity of noscapine and papaverine metabolites as markers of heroin misuse in the context of diamorphine treatment. A survey of urine samples from non-substance misusing patients prescribed diamorphine. Journal of Substance Use 14(2): 133-138, 2009. (17 refs.)

Background: The use of prescribed injectable diamorphine (pharmaceutical heroin) as a treatment for heroin dependence remains controversial. The detection of urinary morphine and 6-monoacetyl-morphine as indicators of street heroin misuse is confounded in patients prescribed diamorphine and there is no alternative biomarker in routine use. A previous paper reported on the gas chromatography-mass spectrometry analysis of over 1000 urine samples from patients of a substance misuse service, and concluded that the detection of papaverine and noscapine metabolites was likely to provide a reasonably sensitive and highly specific means of identifying the use of street heroin in patients prescribed diamorphine. Aims: In this study the potential for the parenteral administration of pharmaceutical diamorphine to give rise to the detection of these putative markers of street heroin in urine is examined. Design: Over a 15-month period, 57 patients from seven hospices in the UK provided pre- and post-diamorphine infusion samples. Samples were analysed by gas chromatography-mass spectrometry using the previously described procedure. Findings: No sample was positive for any of the previously identified markers of street heroin use, that is meconine, desmethylmeconine, hydroxypapaverine, and dihydroxypapaverine. When combined with the results from a pilot study the overall specificity approaches 100% with sensitivity of 56%. Conclusions: These findings support the previously indicated high degree of specificity of noscapine and papaverine metabolites for street heroin misuse. While the sensitivity of such testing is less than that of morphine for heroin misuse, we believe that the detection of these markers offers the best currently available means of objectively determining heroin misuse in patients prescribed diamorphine.

Uchaipichat V; Raungrut P; Chau N; Janchawee B; Evans AM; Miners JO. Effects of ketamine on human udp-glucuronosyltransferases in vitro predict potential drug-drug interactions arising from ketamine inhibition of codeine and morphine glucuronidation. Drug Metabolism and Disposition 39(8): 1324-1328, 2011. (25 refs.)

In this study, the selectivity of UDP-glucuronosyltransferase (UGT) enzyme inhibition by ketamine (KTM) and the kinetics of KTM inhibition of human liver microsomal morphine (MOR) and codeine (COD) glucuronidation were characterized to explore a pharmacokinetic basis for the KTM-opioid interaction. With the exception of UGT1A4, KTM inhibited the activities of recombinant human UGT enzymes in a concentration-dependent manner. However, IC(50) values were < 100 mu M only for UGT2B4, UGT2B7, and UGT2B15. UGT2B7 catalyzes MOR 3- and 6-glucuronidation and the 6-glucuronidation of COD, with an additional substantial contribution of UGT2B4 to the latter reaction. Consistent with the effects of KTM on the activities of recombinant UGT2B enzyme activities, KTM competitively inhibited human liver microsomal MOR and COD glucuronidation. K(i) values for KTM inhibition of MOR 3- and 6-glucuronidation and COD 6-glucuronidation by human liver microsomes supplemented with 2% bovine serum albumin were 5.8 +/- 0.1, 4.6 +/- 0.2, and 3.5 +/- 0.1 mu M, respectively. Based on the derived inhibitor constants, in vitro-in vivo extrapolation was used to predict the effects of anesthetic and analgesic doses of KTM on MOR and COD clearances. Potentially clinically significant interactions (>50% increases in the in vivo area under the curve ratios) with MOR and COD were predicted for anesthetic doses of KTM and for a subanesthetic dose of KTM on COD glucuronidation.

Vendramin A; Sciacchitano AM. Pharmacology and neurochemistry of methadone. (review). Heroin Addiction and Related Clinical Problems 11(3): 11-28, 2009. (118 refs.)

Contrary to what might be thought initially, the pharmacology of methadone is only partly known, and current research continues to investigate into its distinctive aspects. Clinical evidence provides key guidance to pharmacological research on the opiate system; on the other hand, evolving expectations from therapeutic drugs or putative agents for addiction treatment provide a key incentive to the broadening of pharmacological knowledge. Apart from the classic description of receptorial opioid agonism, narcotic blockade and tolerance/withdrawal dynamics, some crucial issues need to be clarified in a comprehensive way. For instance, studies have proved the importance of metabolic polymorphism in treatment planning and offered interpretations of apparent resistance to normal dosages, so authorizing the employment of high dosages on a sound pharmacological basis. Also, dosages should not be regarded as stable through time, especially in the first few months, and clinicians may schedule dose variations that take into account such expected variations while pursuing stabilization. Methadone's action profile in the central nervous system is not exclusively based on opioid receptors, and a thorough knowledge of its 'collateral' effects may explain its beneficial action against specific psychopathological abnormalities. The role of the inactive enantiomer in the context of racemous methadone's tolerability and action profile has also been outlined. Lastly, some of the therapeutic effects of methadone endure without being neutralized by the emergence of tolerance; one of these is its crucial anticraving property. In order to clarify this issue, the mechanisms of cell membrane endocytosis and signal transduction have been illustrated and compared between different opiates.

Viscusi ER; Gambling DR; Hughes TL; Manvelian GZ. Pharmacokinetics of extended-release epidural morphine sulfate: Pooled analysis of six clinical studies. American Journal of Health-System Pharmacy 66(11): 1020-1030, 2009. (32 refs.)

Purpose. A pooled analysis of six clinical studies was conducted to describe the pharmacokinetics of extended-release epidural morphine sulfate. Methods. Data from six clinical studies evaluating extended-release epidural morphine sulfate in volunteers and abdominal or hip surgery patients were pooled and analyzed. Participants age 18 years or older received extended-release epidural morphine sulfate (2.5-40 mg) within 30 minutes of surgery initiation. Most participants received a test dose of 1.5% lidocaine with 1:200,000 epinephrine for epidural space identification 15 minutes before study drug administration. Blood samples were generally collected at 0.5, 2, 4, 8, 12, 18, 24, and 48 hours postinjection. Results. Standard epidural morphine sulfate exhibited a spike in drug release, producing higher peak concentrations (C-max) than 5-mg extended-release epidural morphine sulfate, which produced more prolonged serum morphine concentrations. Using labeled doses of extended-re lease epidural morphine sulfate (10-20 mg), the C-max was comparable to that for 5-mg standard epidural morphine sulfate, whereas the apparent terminal elimination half-life and area under the serum concentration-time curve were twofold to fourfold greater and consistent with dose-proportional exposure. The mean dose-normalized C-max for extended-release epidural morphin; sulfate was 25% higher for women versus men. Administering extended-release epidural morphine sulfate 15 minutes after the test dose mitigated any pharmacokinetic interaction. Extended-release epidural morphine sulfate demonstrated close-related reductions in postoperative fentanyl consumption and pain intensity. Conclusion. A pooled analysis of six studies revealed that extended-release epidural morphine sulfate provided a more prolonged release of morphine compared with standard epidural morphine sulfate. Extended-release epidural morphine sulfate displayed a consistent pharmacokinetic profile among adults, with only slight variability between men and women in C-max, which appeared to be mainly caused by differences in body weight.

Wang H; Li EY; Xu GW; Wang CS; Gong YL; Li P. Intravenous fentanyl is exhaled and the concentration fluctuates with time. Journal of International Medical Research 37(4): 1158-1166, 2009. (18 refs.)

Previous studies have reported that fentanyl is eliminated predominantly by hepatic biotransformation, and that some is eliminated unchanged in urine and stools. No reports have described the elimination of fentanyl via the lungs. In this study, exhaled gas samples from eight anaesthetized patients undergoing cardiac surgery were analysed using solid-phase microextraction (SPME) coupled with gas chromatography-mass spectrometry (GC-MS). Results confirmed that fentanyl was exhaled by patients after intravenous administration, that the concentration of exhaled fentanyl fluctuated with time and peak concentrations were reached approximately 15 - 20 min after intravenous fentanyl administration. Thus, in addition to hepatic biotransformation and elimination via urine and faeces, fentanyl is also eliminated unchanged by the lungs. The potential risk to operating theatre personnel from long-term exposure to low levels of exhaled anaesthetic agents following intravenous administration to patients during surgery warrants further research.

Wang XM; Abdelrahman DR; Zharikova OL; Patrikeeva SL; Hankins GDV; Ahmed MS et al. Bupropion metabolism by human placenta. Biochemical Pharmacology 79(11): 1684-1690, 2010. (54 refs.)

Smoking during pregnancy is the largest modifiable risk factor for pregnancy-related morbidity and mortality. The success of bupropion for smoking cessation warrants its investigation for the treatment of pregnant patients. Nevertheless, the use of bupropion for the treatment of pregnant smokers requires additional data on its bio-disposition during pregnancy. Therefore, the aim of this investigation was to determine the metabolism of bupropion in placentas obtained from nonsmoking and smoking women, identify metabolites formed and the enzymes catalyzing their formation, as well as the kinetics of the reaction. Data obtained revealed that human placentas metabolized bupropion to hydroxybupropion, erythro- and threohydrobupropion. The rates for formation of erythro- and threohydrobupropion exceeded that for hydroxybupropion by several folds, were dependent on the concentration of bupropion and exhibited saturation kinetics with an apparent K-m value of 40 mu M. Human placental 11 beta-hydroxysteroid dehydrogenases were identified as the major carbonyl-reducing enzymes responsible for the reduction of bupropion to threo- and erythrohydrobupropion in microsomal fractions. On the other hand, CYP2B6 was responsible for the formation of OH-bupropion. These data suggest that both placental microsomal carbonyl-reducing and oxidizing enzymes are involved in the metabolism of bupropion.

Wassenaar CA; Dong Q; Wei QY; Amos CI; Spitz MR; Tyndale RF. Relationship between CYP2A6 and CHRNA5-CHRNA3-CHRNB4 variation and smoking behaviors and lung cancer risk. Journal of the National Cancer Institute 103(17): 1342-1346, 2011. (26 refs.)

Genetic variations in the CYP2A6 nicotine metabolic gene and the CHRNA5-CHRNA3-CHRNB4 (CHRNA5-A3-B4) nicotinic gene cluster have been independently associated with lung cancer. With genotype data from ever-smokers of European ancestry (417 lung cancer patients and 443 control subjects), we investigated the relative and combined associations of polymorphisms in these two genes with smoking behavior and lung cancer risk. Kruskal-Wallis tests were used to compare smoking variables among the different genotype groups, and odds ratios (ORs) for cancer risk were estimated using logistic regression analysis. All statistical tests were two-sided. Cigarette consumption (P < .001) and nicotine dependence (P = .036) were the highest in the combined CYP2A6 normal metabolizers and CHRNA5-A3-B4 AA (tag single-nucleotide polymorphism rs1051730 G>A) risk group. The combined risk group also exhibited the greatest lung cancer risk (OR = 2.03; 95% confidence interval [CI] = 1.21 to 3.40), which was even higher among those who smoked 20 or fewer cigarettes per day (OR = 3.03; 95% CI = 1.38 to 6.66). Variation in CYP2A6 and CHRNA5-A3-B4 was independently and additively associated with increased cigarette consumption, nicotine dependence, and lung cancer risk. CYP2A6 and CHRNA5-A3-B4 appear to be more strongly associated with smoking behaviors and lung cancer risk, respectively.

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 in future pain therapies. As advances continue in the genetics of pain and analgesia, pharmacotherapy will depend more on all individualized, targeted approach and less on empiricism.

Zorick T; Mandelkern MA; Lee B; Wong ML; Miotto K; Shahbazian J; London ED. Elevated plasma prolactin in abstinent methamphetamine-dependent subjects. (review). American Journal of Drug and Alcohol Abuse 37(1): 62-67, 2011. (24 refs.)

Background: Methamphetamine (MA) use disorders are pervasive global social problems that produce large medical and public health burdens. Abnormalities in pituitary hormonal regulation have been observed in preclinical models of substance abuse and in human substance abusers. They have, however, not been studied before in MA-dependent human subjects. Objectives: To determine if MA-dependent research volunteers differ from healthy control subjects in plasma levels of adrenocorticotropic hormone (ACTH), cortisol, or prolactin, or in pituitary dopamine D-2 receptor availability during early abstinence from MA. Methods: MA-dependent subjects (N = 31), who were not seeking treatment, resided on an inpatient ward for up to 5 weeks. Abstinence was confirmed by daily urine drug screening. Venous blood was sampled for plasma hormone levels, and positron emission tomography with [F-18] fallypride was performed to determine dopamine D-2 receptor availability during the first week of abstinence. Venous blood was sampled again for hormone levels during the fourth week of abstinence. Matched healthy volunteers (N = 23) participated as a comparison group. Results: MA-dependent and healthy comparison subjects did not differ in plasma ACTH or cortisol levels, but had an elevated plasma prolactin at both the first week and fourth week of abstinence. There was no group difference in pituitary dopamine D-2 receptor availability. Conclusion: MA-dependent individuals have abnormalities in prolactin regulation, which is not likely due to alterations in pituitary dopamine D-2 receptor availability. Scientific significance: MA dependence is associated with elevated prolactin levels, which may contribute to medical comorbidity in afflicted individuals.