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CORK Bibliography: Absorption of Alcohol and Other Drugs

36 citations. January 2000 to present

Prepared: March 2003

Baraona E. Site and quantitative importance of alcohol first-pass metabolism. Alcoholism: Clinical and Experimental Research 24(4): 405-406, 2000. (10 refs.)

This is one in a set of short papers that were presented at a workshop on issues relevant to the absorption, distribution, and elimination of alcohol in non-alcoholics. The meeting was convened by the National Institute on Alcohol Abuse and Alcoholism.

Dale O; Hoffer C; Sheffels P; Kharasch ED. Disposition of nasal, intravenous, and oral methadone in healthy volunteers. Clinical Pharmacology and Therapeutics 72(5): 536-545, 2002. (58 refs.)

Objective: Nasal administration of many opioids demonstrates rapid uptake and fast onset of action. Nasal administration may be an alternative to intravenous and oral administration of methadone and was therefore studied in human volunteers. Methods: The study was approved by the Institutional Review Board of the University of Washington, Seattle. Eight healthy volunteers (6 men and 2 women) aged 19 to 33 years were enrolled after informed written consent was obtained. Subjects received 10 mg methadone hydrochloride nasally, orally, or intravenously on 3 separate occasions in a crossover design. Nasal methadone (50 mg/mL in aqueous solution) was given as a 100-muL spray in each nostril (Pfeiffer BiDose sprayer). Blood samples for liquid chromatography-mass spectrometry analyses of methadone and the metabolite 2-ethyl-1,5- dimethyl-3,3-diphenylpyrrolinium were drawn for up to 96 hours. The methadone effect was measured by noninvasive infrared pupilometry coincident with blood sampling. Results: Nasal uptake of methadone was rapid, with maximum plasma concentrations occurring within 7 minutes. The maximum effects of intravenous, nasal, and oral methadone, on the basis of dark-adapted pupil diameter, were reached in about 15 minutes, 30 minutes, and 2 hours, respectively. The respective durations were 24, 10, and 8 hours. Both nasal and oral bioavailabilities were 0.85. Subjects reported that nasal methadone caused a burning sensation. Conclusions: Nasal administration of methadone results in rapid absorption and onset of effect and high bioavailability, which was greater than that reported for other nasal opioids, with a similar duration of effect. Nasal administration may be an alternative route of methadone administration; however, improved formulations are desirable to reduce nasal irritation.

D'Alessandro A; Benowitz NL; Muzi G; Eisner MD; Filiberto S; Fantozzi P; Montanari L; Abbritti G. Systemic nicotine exposure in tobacco harvesters. Archives of Environmental Health 56(3): 257-263, 2001. (30 refs.)

Several epidemics of nicotine intoxication have been described among tobacco harvesters; however, little is known about nicotine absorption under typical working conditions. To assess systemic nicotine absorption during a regular working shift, the authors performed an observational field study. Included in the study were 10 healthy, nonsmoking, female tobacco harvesters and a control group of 5 healthy, nonsmoking, female hospital workers. Nicotine and cotinine were measured in sequential samples of blood and urine during a regular workshift. Blood nicotine levels rose from a nadir value of 0.79 +/- 0.12 ng/ml to a peak value of 3.45 +/- 0.84 ng/ml (p <.05 [Tukey's modified t test]) in the exposed group. In the control group, levels were stable at 0.1 +/- 0.1 ng/ml (p <.01). Moreover, the mean blood nicotine level measured 3 mo following the end of exposure in 6 of 10 exposed subjects was 0.24 +/- 0.12 ng/ml (p <.01). Corresponding higher values of urine nicotine and urine cotinine were observed in the exposed versus control group (comparative p values were <.01 and <.05, respectively). Overall, tobacco harvesters absorbed approximately 0.8 mg of nicotine daily. Given that nicotine can induce adverse health effects, the authors believe that prevention of nicotine absorption in tobacco harvesters should be sought and that workers should be informed about occupational risks.

Desager JP; Golnez JL; De Buck C; Horsmans Y. Watercress has no importance for the elimination of ethanol by CYP2E1 inhibition. Pharmacology and Toxicology 91(3): 103-105, 2002. (16 refs.)

Watercress, a cruciferous vegetable, is known to inhibit the metabolism of several CYP2E1 substrates such as paracetamol and chlorzoxazone. Since ethanol and its metabolite, acetaldehyde, are CYP2E1 substrates, the influence of watercress on ethanol and acetaldehyde was investigated in healthy human volunteers. According to a randomized crossover design, ethanol and acetaldehyde pharmacokinetic parameters were determined in 9 persons at 3 occasions: without watercress and after watercress ingestion preceding ethanol consumption from 1 or 10.5 hr, respectively Ethanol t(max) occurred significantly later when watercress was ingested I hr before ethanol ingestion. Likewise, acetaldehyde C-max was significantly higher whereas acetaldehyde AUCs were increased by watercress but not significantly All other ethanol and acetaldehyde pharmacokinetic parameters were similar between the 3 treatments. In healthy volunteers, no major watercress effect was observed on ethanol clearance but a weak inhibiting effect on acetaldehyde metabolism is possible. Ethanol absorption is also delayed by single ingestion of watercress immediately preceding ethanol consumption.

Frolich M; Giannotti A; Modell JH. Opioid overdose in a patient using a fentanyl patch during treatment with a warming blanket. Anesthesia and Analgesia 93(3): 647-648, 2001. (5 refs.)

Fentanyl transdermal systems (FTS) are being used effectively for treating chronic pain for which prolonged opioid use is often required. Transdermal drug delivery is marketed to be safe and to maintain plasma concentrations at a steady state. However, there is evidence that these drug delivery systems, when exposed to heat, may result in increased fentanyl release causing hypoventilation. The authors report a patient who showed classic symptoms of excessive opioids when using a FTS while an upper-body-warming blanket was used. Her medications were transdermal fentanyl (75 痢/hr), gabapentin 600 mg once daily, baclofen 5 mg three times a day, sertraline 50 mg, once daily, zolpidem as needed for insomnia, and acetaminophen/oxycodone 325 mg/5 mg, for breakthrough pain. The patient had a lumbar epidural catheter placed at L3-4 for intra- and postoperative analgesia. This case illustrates a potentially serious side effect of FTS. The sequence of events and the absence of other factors that could have resulted in the clinical scenario presented here strongly point toward the systemic effects of a fentanyl overdose. There are few case reports of adverse reactions related to the use of a fentanyl patch. This case is the first account of an actual overdose related to FTS, which occurred in the operating room in a patient whose vital signs were continuously monitored. The pharmacology of transdermal delivery systems has been studied carefully. Based on pharmacokinetic observations, the fentanyl absorption is dependent on diffusion characteristics of the patch as well as the skin. The patient's core temperature had decreased to 34.9。 with the associated skin temperature probably being lower. On exposure of the skin to the heating blanket, a significant increase in skin perfusion can be expected. The increased cutaneous perfusion is likely to result in increased systemic absorption of fentanyl from the intracutaneous fentanyl depot. Although we did not measure fentanyl plasma concentrations, we believe that this mechanism was responsible for increased systemic fentanyl levels and the observed symptoms of opioid overdose in this patient. On the basis of our experience, we recommend close perioperative monitoring of patients medicated with a FTS, particularly if external heat is applied.

Furst RT. The re-engineering of heroin: An emerging heroin "cutting" trend in New York City. Addiction Research 8(4): 357-379, 2000. (33 refs.)

The objective of this paper is to identify and to make sense out of changes in the use of adulterants and diluents found in samples of street bags of heroin collected in New York City. An analysis of the ratio of adulterants to diluents was conducted. Findings indicate that a change in the ratio of adulterants to diluents has occurred, notably, an increase in the use of adulterants from 1991-1996. This suggests that foreign producer/distributor and retail sellers are cutting heroin to psychaoctively enhance its' effect. One of the adulterants used (theophylline) has the capability of enhancing the intranasal absorption of heroin into the bloodstream; thereby enhancing the "high" of heroin and possibly hastening dependency. These findings are based on an analysis of 406 chemical assays of street bags of heroin purchased by informants for the Drug Enforcement Administration (DEA), Domestic Monitor Purities (DMP) program. In addition, ethnographic observations of injecting drug users (IDUs) and interviews with street dealers are utilized to augment forensic analysis. Change in the ratio of adulterants to diluents has implications for the marketing of heroin and may have medical and health consequences for heroin users.

Gaulier JM; Merle G; Lacassie E; Courtiade B; Haglund P; Marquet P et al. Fatal intoxications with chloral hydrate. Journal of Forensic Sciences 46(6): 1507-1509, 2001. (23 refs.)

This article reports toxicological findings in two fatalities after voluntary ingestion of chloral hydrate, a sedative-hypnotic drug. The first case, an alcohol-dependent man treated with chloral hydrate syrup to which he was dependent, was discovered comatose and in respiratory arrest. Death occurred on the 9th day of hospitalization following cerebral edema. The second case, an alcohol-dependent woman who was depressed and epileptic, was admitted to the intensive care unit with heart and respiratory failure following chloral hydrate absorption. She died 3 days later after a deep coma. In these two cases, chloral hydrate intoxication was confirmed by toxicological analysis: chloral hydrate and its major metabolite trichloroethanol were identified and determined in serum and urine using headspace capillary gas chromatography-mass spectrometry. The concentrations measured were compared with those found in previously published fatalities. The analytical method used can be proposed for both clinical and forensic cases.

Gentry RT. Determinants and analysis of blood alcohol concentrations after social drinking. Alcoholism: Clinical and Experimental Research 24(4): 399-399, 2000. (0 refs.)

This is an introduction to a series of short papers that were presented at a workshop on issues relevant to the absorption, distribution, and elimination of alcohol in non-alcoholics. The meeting was convened by the National Institute on Alcohol Abuse and Alcoholism.

Gentry RT. Effect of food on the pharmacokinetics of alcohol absorption. Alcoholism: Clinical and Experimental Research 24(4): 403-404, 2000. (10 refs.)

Gold MS; Tabrah H; Frost-Pineda K. Psychopharmacology of MDMA (Ecstasy). Psychiatric Annals 31(11): 675-681, 2001. (29 refs.)

Haber PS. Metabolism of alcohol by the human stomach. Alcoholism: Clinical and Experimental Research 24(4): 407-408, 2000. (11 refs.)

Hendriks VM; van den Brink W; Blanken P; Bosman IJ; van Ree JM. Heroin self-administration by means of 'chasing the dragon': Pharmacodynamics and bioavailability of inhaled heroin. European Neuropsychopharmacology 11(3): 241-252, 2001. (35 refs.)

In this controlled clinical study, the bioavailability and pharmacodynamics of inhaled heroin are evaluated and compared between 'chasing the dragon' and inhalation from a heating device, and at three dose levels, 25, 50 and 100 mg heroin, in two separate study phases. In study phase I, no differences between the inhalation methods were detected on any of the physiological or behavioral measures, nor in bioavailability. Subjectively, the participants had a strong preference for the method of chasing. which was therefore used in study phase 2. In phase 2, heroin produced a dose-related increase in subjective drug-liking, body temperature and heart rate, and a clear, dose-related decline in reaction time. Linearly dose- related differences were found in the amount of total morphine in urine, amounting to an average of 45% of the parent heroin base received. Based on these findings, it is concluded that chasing is quite an effective route of heroin administration, producing rapid, dose-related subjective and objective effects and a sufficiently high and reproducible bioavailability.

Jones AW. Aspects of in-vivo pharmacokinetics of ethanol. Alcoholism: Clinical and Experimental Research 24(4): 400-402, 2000. (12 refs.)

Kalant H. Effects of food and body composition on blood alcohol curves. Alcoholism: Clinical and Experimental Research 24(4): 413-414, 2000. (9 refs.)

Kinoshita H; Ijiri I; Ameno S; Kubota T; Zhang X; Hishida S; Ameno K. Cholinergic nerves mediate acetaldehyde action in the gastrointestinal tract. Alcohol and Alcoholism 36(5): 377-380, 2001. (23 refs.)

The regulation mechanism of inhibition of intestinal ethanol absorption induced by high acetaldehyde (AcH) concentration in blood was investigated. We used atropine (AT), atropine methylbromide (ATMB), pirenzepine (PI), bethanechol (BE) and pilocarpine (PL) with or without cyanamide (CY; a potent inhibitor of aldehyde dehydrogenase, which induces high AcH concentration in blood). The K- a (absorption rate constant) value after the CY-alone pretreatment was significantly lower than that in controls. In the high AcH- induced cases, the values of K-a in AT and ATMB pretreatments were similar to controls, but the value of K-a in PI pretreatment was lower than that in controls. The values of K-a in the case of BE pretreatment with and without high AcH levels were lower than in controls. The K-a value in the PL with CY was significantly lower than that with CY alone. However, its action was blocked by ATMB pretreatment. These results suggest that high blood AcH concentrations inhibit intestinal ethanol absorption through the peripheral cholinergic nerves via muscarinic receptors, except for the muscarinic M-1 receptor, compared to other subtypes of muscarinic receptors.

Klockhoff H; Naslund I; Jones AW. Faster absorption of ethanol and higher peak concentration in women after gastric bypass surgery. British Journal of Clinical Pharmacology 54(6): 587-591, 2002. (30 refs.)

Aims To investigate the absorption, distribution and elimination of ethanol in women with abnormal gut as a result of gastric bypass surgery. Patients who undergo gastric bypass for morbid obesity complain of increased sensitivity to the effects of alcohol after the operation. Methods Twelve healthy women operated for morbid obesity at least 3 years earlier were recruited. Twelve other women closely matched in terms of age and body mass index (BMI) served as the control group. After an overnight fast each subject drank 95% v/v ethanol (0.30 g kg(-1) body weight) as a bolus dose. The ethanol was diluted with orange juice to 20% v/v and finished in 5 min. Specimens of venous blood were taken from an indwelling catheter before drinking started and every 10 min for up to 3.5 h post-dosing. The blood alcohol concentration (BAC) was determined by headspace gas chromatography. Results The maximum blood-ethanol concentration (C (max) ) was 0.741 +/- 0.211 g l(-1) (+/- s.d.) in the operated group compared with 0.577 +/- 0.112 g l(-1) in the controls (mean difference 0.164 g l(- 1) , 95% confidence interval (CI) 0.021, 0.307). The median time to peak (t (max) ) was 10 min in the bypass patients compared with 30 min in controls (median difference -15 min (95% CI -10, -20 min). At 10 and 20 min post-dosing the BAC was higher in the bypass patients (P < 0.05) but not at 30 min and all later times (P > 0.05). Other pharmacokinetic parameters of ethanol were not significantly different between the two groups of women (P > 0.05). Conclusions The higher sensitivity to ethanol after gastric bypass surgery probably reflects the more rapid absorption of ethanol leading to higher C-max and earlier t(max) . The marked reduction in body weight after the operation might also be a factor to consider if the same absolute quantity of ethanol is consumed.

Levine B; Smialek JE. Status of alcohol absorption in drinking drivers killed in traffic accidents. Journal of Forensic Sciences 45(1): 3 -6, 2000. (11 refs.)

One issue which constantly confronts the forensic toxicologist in drinking driver cases is the relationship between the breath or blood alcohol concentration (AC) of the driver at the time of an event such as a traffic stop or an accident and the AC measured at a time subsequent to the event. In theory, the AC can be rising, on a plateau or declining at the time of the event. Several studies have indicated that the overwhelming majority of drinking drivers are on a plateau or are post-absorptive at the time of the event. In this study, driver fatality cases investigated by the Office of the Chief Medical Examiner, State of Maryland during a three-year period were reviewed. Included in this study were cases positive for alcohol in the blood at a cutoff of 0.01 g/dL and death occurring within 15 min of the accident. In fact, many of these deaths were instantaneous or near instantaneous based on the injuries documented by the medical examiner at autopsy. The blood and urine were analyzed for alcohol by head-space gas chromatography and urine AC to blood AC ratios were calculated. A total of 129 cases were included in this study. Eleven of the 129 cases (8.5%) had urine to blood AC ratio less than 1.0. It is likely that these individuals were in the absorptive phase at the time that the accident occurred. Thirty-two cases had a urine to blood AC ratio between 1.0 and 1.2 inclusive. In these cases, the subject could be viewed as in the plateau phase of the blood AC versus time curve. The remaining 86 cases had a urine to blood AC ratio greater than 1.2. This suggests that these individuals were in the post-absorptive state at the time of the accident. The information acquired from this study provides additional evidence to support the notion that the vast majority of individuals are not in the absorptive phase at the time of a traffic stop or an accident

Levitt MD; Levitt D. Use of a two-compartment model to predict ethanol metabolism. Alcoholism: Clinical and Experimental Research 24(4): 409-410, 2000. (4 refs.)

Lieber CS. Ethnic and gender differences in ethanol metabolism. Alcoholism: Clinical and Experimental Research 24(4): 417-418, 2000. (16 refs.)

Littleton J; Little H. Interactions between alcohol and nicotine dependence: A summary of potential mechanisms and implications for treatment. Alcoholism: Clinical and Experimental Research 26(12): 1922-1924, 2002. (8 refs.)

This article summarizes the potential mechanisms which underlie the interactions between alcohol and nicotine dependence. There is discussion of pharmacokinetic interactions that influence metabolism, absorption, and distribution. Also liver metabolism of both drugs may be altered through cytochrome induction after long-term exposure to both. There are also factors at the molecular level that need be considered, the impact on various neurotransmitters, and alcohol's effects on nicotinic receptors. It is also noted that, in contradistinction to the view that specific mechanisms are causal to the use of both drugs, there is the view that the phenomenon maybe more indicative of a functional interaction. For example, possibly the cognitive enhancing effects of nicotine may offset the cognitive inhibition resulting from alcohol use. The role of conditioning in this phenomenon is reviewed. The author notes in conclusion, that whatever the basis the strength of dependence is greater among co-abusers.

Lukas SE; Orozco S. Ethanol increases plasma Delta(9)-tetrahydrocannabinol (THC) levels and subjective effects after marihuana smoking in human volunteers. Drug and Alcohol Dependence 64(2): 143-149, 2001. (36 refs.)

Marihuana and alcohol are often used together, yet little is known about why they are combined. Male volunteers were assigned to one marihuana treatment group (placebo, low or moderate dose Delta (9)- tetrahydrocannabinol (THC)) and, on three separate study days, they also drank a different dose of ethanol (placebo, 0.35 or 0.7 g/kg). Plasma THC levels and changes in subjective mood states were recorded for 90 min after smoking. For many of the drug combinations, when subjects consumed ethanol they detected marihuana effects more quickly, reported more episodes of euphoria and had higher plasma THC levels than when they consumed placebo ethanol. These data suggest that ethanol may increase the absorption of THC resulting in an increase in the positive subjective mood effects of smoked marihuana and contributing to the popularity of this drug combination.

Mason BJ; Goodman AM; Dixon RM; Hameed MHA; Hulot T; Wesnes K et al. A pharmacokinetic and pharmacodynamic drug interaction study of acamprosate and naltrexone. Neuropsychopharmacology 27(4): 596-606, 2002. (71 refs.)

Acamprosate and naltrexone have each demonstrated safety and efficacy for alcohol dependence in placebo-controlled clinical trials. There is scientific and clinical interest in evaluating these drugs in combination, given their high tolerability, moderate effect sizes, different pharmacological profiles and potentially different effects on drinking outcomes. Thus, this is the first human pharmacokinetic and pharmacodynamic drug interaction study of acamprosate and naltrexone. Twenty-four normal, healthy adult volunteers participated in a double-blind, multiple dose, within subjects, randomized, 3-way crossover drug interaction study of the standard therapeutic dose of acamprosate (2 g/d) and the standard therapeutic dose of naltrexone (50 mg/d), given alone and in combination, with seven days per treatment condition and seven days washout between treatments. Blood samples were collected on a standardized schedule for pharmacokinetic analysis of naltrexone, 6-beta-naltrexol, and acamprosate. A computerized assessment system evaluated potential drug effects on cognitive functioning. Coadministration of acamprosate with naltrexone significantly increased the rate and extent of absorption of acamprosate, as indicated by an average 33% increase in acamprosate-maximum plasma concentration, 33% reduction in time to maximum plasma concentration, and 25% increase in area under the plasma concentration-time curve. Acamprosate did not affect the pharmacokinetic parameters of naltrexone or 6-beta-naltrexol. A complete absence of negative interactions on measures of safety and cognitive function supports the absence of a contraindication to co-administration of acamprosate and naltrexone in clinical practice.

McDonald T; Berkowitz R; Hoffman WE. Plasma naltrexone during opioid detoxification. Journal of Addictive Diseases 19(4): 59-64, 2000. (6 refs.)

Orogastric naltrexone is used for opioid detoxification, but it is not known how gastric absorption affects plasma concentrations of the drug. We measured plasma naltrexone during orogastric naltrexone, given in repeated doses of 12.5 mg, 25 mg, 50 mg and 50 mg. Plasma naltrexone was measured after each naltrexone dose. The increase in plasma naltrexone was highly variable between patients during orogastric administration. Adequate detoxification was, questioned in 4 of 10 patients because plasma naltrexone did not increase above 5 ng/ml. There was a negative correlation between plasma naltrexone and the presence of withdrawal symptoms on the day after the procedure (r = - 0.78, P < 0.05). These results show that the increase in plasma naltrexone is variable during orogastric administration and this may impair successful detoxification.

Mezey E. Influence of sex hormones on alcohol metabolism. Alcoholism: Clinical and Experimental Research 24(4): 421-421, 2000. (5 refs.)

Molander L; Lunell E. Pharmacokinetic investigation of a nicotine sublingual tablet. European Journal of Clinical Pharmacology 56(11): 813-819, 2001. (22 refs.)

Objective: To evaluate the pharmacokinetics of a new 2-mg nicotine sublingual tablet under varying conditions of use. Methods: The pharmacokinetics of the 2-mg nicotine sublingual tablet were investigated in four separate studies involving healthy adult volunteer smokers: (1) a multiple-dose comparison with 2-mg nicotine chewing gum (n=24; 13 males, 11 females), (2) a dose-proportionality study comparing single doses of 2, 4 and 6 mg (n=21, 10 males, 11 females), (3) an evaluation of the effect of incorrect tablet use, i.e. chewing the tablet followed by either immediate or delayed swallowing (n = 19, 10 males, 9 females), and (4) the effect of oral and gastric pH on nicotine absorption from the tablet (n=20; 11 males, 9 females). Study parameters were maximal plasma concentration (C-max), time to C-max (t(max)), and area under the plasma concentration-time curve (AUC). Results: The plasma nicotine profiles were similar following repeated administration of the sublingual tablet and the 2-mg nicotine chewing gum (mean C-max 13.2 versus 14.4 ng/ml, median t(max) 20 versus 20 min, mean AUC(11-12) 12.4 versus 13.5 ng/ml per hour) with no statistically significant difference between the two treatments. The pharmacokinetics of the 4- and 6-mg doses were non-linear compared to the 2-mg dose, probably as a result of more of the dose being swallowed and undergoing first-pass metabolism in the liver. The mean C-max for the 2-, 4- and 6-mg dose was 3.8 +/- 1.0, 6.8 +/- 2.1, and 9.0 +/- 3.3 ng/ml, respectively, and in terms of dose proportionality the relative bioavailability of the 4- and 6-mg dose was 0.82 and 0.71, respectively. Incorrect tablet use, i.e. chewing the tablet and immediate swallowing decreased nicotine bioavailability both in terms of rate and extent. Mean C-max was 12.1 ng/ml (correct use), 10.3 ng/ml (chewing and immediate swallowing), and 12.1 ng/ml (chewing and delayed swallowing). Corresponding mean values for AUC(9-10) were 11.6, 9.6 and 11.2 ng/ml per hour. There were no significant differences between 'alkaline mouth' versus control,'acidic mouth' versus control or 'alkaline stomach' versus control, but the rate of nicotine absorption was increased at alkaline compared to acidic oral pH (mean C-max 6.1 versus 4.9 ng/ml, P = 0.003; median t(max) 60 versus 90 min, P = 0.0002). Conclusion: The pharmacokinetic profile of the nicotine 2-mg tablet was similar to that of the 2-mg nicotine chewing gum. Absorption of nicotine from the tablet was nonlinear at higher doses (two or three tablets). Chewing the tablet and keeping the remains in the mouth or concurrent use of acidic beverages or antacids are equivalent to recommended sublingual use during normal oral pH conditions.

Norberg A; Bratteby LE; Gabrielsson J; Jones AW; Fan H; Hahn RG. Do ethanol and deuterium oxide distribute into the same water space in healthy volunteers? Alcoholism: Clinical and Experimental Research 25(10): 1423-1430, 2001. (43 refs.)

Background: The volume of distribution at steady state for ethanol (V- ss) is thought to be identical to the total body water (TBW). We compared a two-compartment pharmacokinetic model with parallel Michaelis-Menten and first-order renal elimination with the classical one-compartment zero-order elimination model. Ethanol concentration- time profiles were established for breath, venous blood, and urine. The values of V-ss obtained for ethanol were compared with TBW determined by deuterium oxide dilution. Methods: Sixteen healthy volunteers each received a 30-min intravenous infusion of ethanol on two occasions. Ethanol was measured in breath by a quantitative infrared analyzer and in blood and urine by headspace gas chromatography. Deuterium oxide was given as an intravenous injection and measured in serum by isotope-ratio mass spectrometry. Components of variation were calculated by ANOVA to determine the precision of the estimates of V-ss and TBW. Results: Mean TBW, determined by deuterium oxide dilution, was 44.1 +/-3.9 liters ( SD) for men, corresponding to 0.61 liters/kg, and 37.4 +/-3.2 liters for women, or 0.54 liters/kg. Estimates of V-ss from blood-ethanol pharmacokinetics were 87.6% of TBW according to isotope dilution and 84.4% for breath analysis with the two- compartment model. This compares with 95.1% and 95.4% for blood and breath alcohol, respectively, when the classical zero-order kinetic analysis is used. The precision of the estimates of V-ss and TBW was between 1.56 and 2.19 liters (95% confidence interval). Conclusions: Ethanol does not distribute uniformly into the TBW. The precision of measuring V-ss by ethanol dilution was comparable to estimates of TBW by isotope dilution. Results of noninvasive breath ethanol analysis compared well with use of venous blood for estimating V-ss. The sophisticated two-compartment model was much superior to the classical one-compartment model in explaining the total concentration-time course of intravenously given ethanol.

Patten CA. A critical evaluation of nicotine replacement therapy for teenage smokers. (review). Journal of Child & Adolescent Substance Abuse 9(4): 51-75, 2000. (100 refs.)

The purpose of this review is to evaluate the appropriateness and feasibility of nicotine replacement therapy (NRT) in teenage smokers. In this paper, available forms of NRT, the theoretical rationale and efficacy of NRT, ethical considerations, and the feasibility of NRT in teenage smokers are addressed. Although there is a need to better understand the addiction process in adolescents, it is clear that teens have several characteristics similar to adult nicotine dependent smokers. These observations form the basis of the rationale for the use of NRT in teenagers. Only one report has examined the efficacy of NRT in teen smokers. This study observed a stop rate of 4.5% at six-months in 22 subjects using the nicotine patch. In addition to the potential benefits of NRT, ethical issues have been raised regarding the appropriate use of NRT in teenage smokers. Ethical considerations of NRT use in adult smokers, which need further study in adolescents, are nicotine absorption, long-term use, potential for side effects, concomitant smoking, use in pregnant smokers, and abuse liability in nonsmokers and light, intermittent smokers. The feasibility of NRT in adolescent smokers is also discussed, including its acceptability, convenience, social approval, cost, and availability. Many teens are nicotine dependent and additional clinical trials are warranted to evaluate whether NRT provides benefit to adolescent smokers. In addition, further research is needed to study adjunctive behavioral interventions tailored to the developmental and psychosocial needs of adolescents.

Pendlington RU; Whittle E; Robinson JA; Howes D. Fate of ethanol topically applied to skin. Food and Chemical Toxicology 39(2): 169-174, 2001. (7 refs.)

Driving a vehicle while having a blood alcohol concentration (BAC) higher than 80 mg/100 ml is illegal in the United Kingdom. Because future legislation might significantly reduce the legal BAC limit, the authors assessed the potential systemic dose of ethanol from using alcohol-based aerosol sprays by measuring the evaporation of carbon 14-labeled ethanol from the skin surface, the in vitro penetration of ethanol through excised pig skin, and the BAC of human volunteers (N = 16) after simulated use of an alcohol-based deodorant spray. Evaporation rates from polyethylene backed paper and whole pig skin were similar (t1/2 = 13.6 sec and 11.7 seconds respectively) while that from glass was longer (t1/2 = 24.8 seconds). Ethanol penetrated pig skin at a faster rate in occluded cells than in non-occluded cells (2.19 mg/square cm and 0.10 mg/square cm in 24 hours respectively). At the maximum flux seen in this experiment under occlusion, the amount of ethanol penetrating from a 1 square-meter area of skin would result in a BAC of about 4 mg percent in a 70-kg man. No alcohol was detectable in any of the blood samples taken from 16 human volunteers after they used an alcohol-based spray. The findings indicate that formulations that deliver ethanol to the skin are highly unlikely to result in a significant BAC in the user.

Rentsch KM; Kullak-Ublick GA; Reichel C; Meier PJ; Fattinger K. Arterial and venous pharmacokinetics of intravenous heroin in subjects who are addicted to narcotics. Clinical Pharmacology and Therapeutics 70(3): 237-246, 2001. (24 refs.)

Background: In Switzerland, medical prescription of heroin (diacetylmorphine) is currently being evaluated as a treatment option for heavily dependent addicts. Therefore the diacetylmorphine pharmacokinetics in opioid-addicted patients was studied. Methods: Three different diacetylmorphine doses (up to 210 mg) and 20 mg deuterium-labeled morphine (morphine-d3) were administered intravenously to 8 heroin-addicted patients. Arterial and venous plasma samples were collected, and diacetylmorphine, monoacetylmorphine, morphine, morphine-3-glucuronide, morphine-6- glucuronide, and morphine-d3 plasma concentrations were measured by liquid chromatography-mass spectrometry. Results: Maximal arterial concentrations of diacetylmorphine, monoacetylmorphine, and morphine were 2.4, 5.4, and 1.4 times higher and occurred 2 to 3 minutes earlier than maximal venous concentrations. Venous areas under the concentration-time curves (AUC) of diacetylmorphine and monoacetylmorphine were 35% and 26% lower than arterial AUC values, whereas for morphine the venous AUC was 15% higher. Morphine-3-glucuronide and morphine-6-glucuronide exhibited no arteriovenous differences. AUCs for diacetylmorphine, monoacetylmorphine, and morphine increased linearly with dose: Diacetylmorphine was completely metabolized to morphine. Substantial morphine input into the arterial circulation persisted for up to 90 minutes. The arterial clearances of diacetylmorphine, monoacetylmorphine, and morphine-d3 were 8.7 +/- 2.6, 6.7 +/- 1.6, and 2.3 +/- 0.3 L/min, respectively. The arterial half-lives of diacetylmorphine and morphine-d3 were 2.4 +/- 0.8 and 88 +/- 21 minutes, respectively. Conclusions: These data indicate that substantial arteriovenous differences exist for diacetylmorphine and metabolite kinetics, that the pharmacokinetics of diacetylmorphine and metabolites is linear even in the high dose range used by opioid addicts, and that not only diacetylmorphine but also monoacetylmorphine is substantially metabolized peripherally to morphine.

Roine R. Interaction of prandial state and beverage concentration on alcohol absorption. Alcoholism: Clinical and Experimental Research 24(4): 411-412, 2000. (7 refs.)

Roset PN; Farre M; de la Torre R; Mas M; Menoyo E; Hernandez C; Cami J. Modulation of rate of onset and intensity of drug effects reduces abuse potential in healthy males. Drug and Alcohol Dependence 64(3): 285-298, 2001. (40 refs.)

Low, medium, and high doses of flunitrazepam were tested in three independent randomized, double-blind, balanced cross-over, placebo- con trolled trials to study the influence of rate of onset of effects and dose administered on its acute effects. Three groups of 12 healthy male volunteers received six oral doses of placebo or flunitrazepam in slow and fast onset conditions as follows: six capsules of 0.16 mg (slow) and a single capsule of 0.8 mg (fast) in the low dose trial; six 0.25 mg (slow) and a single 1.25 mg (fast) capsules for medium dose; and six 0.4 mg (slow) and a single 2 mg (fast) capsule for high dose. At each dose level, slow or fast increasing flunitrazepam plasma concentrations lead to similar peak levels, but induced differential subjective and behavioral effects. In addition to objective and subjective sedation, flunitrazepam induced some pleasurable feelings, which were more intense in the fast than in the slow conditions. At the highest dose, unpleasant sedative effects surmounted positive effects, while at the lowest dose pleasurable effects were of low intensity. At the medium dose, the balance between pleasurable and unpleasant feelings resulted in euphorigenic effects, which were evident in the fast condition but were blunted in the slow condition.

Schneider NG; Olmstead RE; Franzon MA; Lunell E. The nicotine inhaler: Clinical pharmacokinetics and comparison with other nicotine treatments. Clinical Pharmacokinetics 40(9): 661-684, 2001. (118 refs.)

Nicotine inhaled in smoke is the most rapid form of delivery of the drug. With smoking, arterial boli and high venous blood nicotine concentrations are produced within seconds and minutes. respectively. The potency of nicotine as the primary reinforcement in tobacco addiction is attributed to this rapid rate of delivery. By design, nicotine treatments reduce the rate and extent of drug delivery for weaning from nicotine during smoking cessation. Theoretically, they prevent relapse by reducing withdrawal and craving associated with the abrupt cessation of cigarettes. The nicotine inhaler treats the complexity of smoking through weaning both from the drug and from the sensory/ritual components associated with smoking. The inhaler is 'puffed' but not lit and there is considerable 'puffing' required to achieve slower rising and lower nicotine concentrations. These factors allow it to be used as a nicotine reduction treatment. One inhaler contains 10mg of nicotine (and 1mg of menthol) of which 4mg of nicotine can be extracted and 2mg are systemically available. Shallow or deep 'puffing' results in similar nicotine absorption. Nicotine is delivered mainly to the oral cavity, throat and upper respiratory tract with a minor fraction reaching the lungs. This was confirmed with positron emission tomography and by assessment of arterial concentrations. A single inhaler can be used for one 20-minute period of continuous puffing or periodic use of up to 400 puffs per inhaler. With controlled puffing in laboratory testing, venous plasma nicotine concentrations from a single inhaler puffed 80 times over 20 minutes averaged 8.1 mug/L at 30 minutes. Lower concentrations of 6.4 to 6.9 mug/L have been reported for self-administration under clinical conditions. The time to peak plasma concentrations varies but is always significantly longer than with cigarette delivery. Estimates of nicotine intake from cotinine concentrations were higher than expected (60 to 70% of baseline smoking concentrations). This elevation may be due to the swallowing of nicotine and subsequent first-pass biotransformation to cotinine. In general, venous blood nicotine concentrations are considerably lower than with smoking and are within the range observed for other nicotine reduction therapies. Efficacy trials show consistent superiority of the inhaler over placebo. Despite the 'cigarette-like' appearance of the inhaler and the associated sensory/ritual elements, little treatment dependence or abuse has been reported. This is attributed to the slow rise time and low nicotine blood concentrations. The inhaler is a valuable addition to treatment of tobacco dependence and can be used alone or with other treatments.

Shoaf SE. Pharmacokinetics of intravenous alcohol: Two compartment, dual Michaelis-Menten elimination. Alcoholism: Clinical and Experimental Research 24(4): 424-425, 2000. (4 refs.)

Swift R. Transdermal alcohol measurement for estimation of blood alcohol concentration. Alcoholism: Clinical and Experimental Research 24(4): 422-423, 2000. (3 refs.)

Thomasson H. Alcohol elimination: Faster in women? Alcoholism: Clinical and Experimental Research 24(4): 419-420, 2000. (11 refs.)

Toennes SW; Kauert GF. Excretion and detection of cathinone, cathine, and phenylpropanolamine in urine after kath chewing. Clinical Chemistry 48(10): 1715-1719, 2002. (21 refs.)

Introduction: The stimulating herbal drug kath is uncommon in most countries, and information on its detection and interpretation of analytical results is limited. Therefore, a study with kath was carried out to compare the efficiencies of different analytical techniques used to detect drug use. Methods: Four volunteers chewed kath leaves for 1 h; urine samples were collected up to 80 It afterward and analyzed by the Abbott fluorescence polarization immunoassay (FPIA), the Mahsan-AMP300 on- site immunoassay, the Bio-Rad Remedi HS HPLC system with photodiode array detection (DAD), and gas chromatography-mass spectrometry (GC- MS). Results: FPIA gave negative results, whereas positive results were obtained with the Mahsan test during the first day. With HPLC, one peak could be observed up to 50 It, but its DAD spectrum could not be identified by the system. Further investigations indicated that the kath alkaloids coeluted and produced a mixed DAD spectrum. With GC- MS, the specific kath ingredient cathinone was detected up to 26 h, whereas cathine and norephedrine were still detectable in the last samples. Maximum concentrations of cathinone, cathine, and norephedrine in urine samples from the study were 2.5, 20, and 30 mg/L, respectively, whereas in authentic cases the concentrations were much higher. Conclusion: GC-MS is superior to the screening techniques Mahsan- AMP300 and Remedi with respect to specificity and sensitivity for the detection of kath use in urine.