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Background Transdermal nicotine in doses up to 21 mg/24 hr is used to facilitate smoking cessation. However, this dose does not achieve the nicotine plasma levels seen among heavy smokers, and underdosing may be one of the reasons for the limited efficacy of transdermal nicotine. There are some concerns about the adverse cardiovascular effects of nicotine, especially with concomitant smoking. Treatment with higher doses of transdermal nicotine has been proposed for highly dependent smokers, but the effects of such treatment on the cardiovascular system have not been determined. The objective of this study was to determine the cardiovascular effects of high-dose transdermal nicotine with concomitant smoking. Methods Twelve healthy male smokers received three doses of transdermal nicotine (21, 42, and 63 mg/24 hr) and placebo, each for 5 days, in a balanced order. The subjects smoked during the first 4 days of each treatment and abstained from smoking during the fifth day. Ambulatory 24-hour daytime and nighttime heart rate and blood pressure values were determined for each treatment; plasma nicotine, cotinine, and carboxyhemoglobin levels and urinary catecholamines with aldosterone were measured on days 4 and 5. The data were compared by means of repeated-measures ANOVA. Results There was no difference in heart rate or blood pressure and no changes in the pattern of circadian variations with various transdermal nicotine doses compared with smoking alone, consistent with the development of tolerance. Urinary epinephrine level was significantly higher (p < 0·05) with transdermal nicotine compared with no nicotine but was not higher with transdermal nicotine and smoking compared with smoking alone. No change was found in fibrinogen and lipid profiles with different nicotine doses. Conclusions High-dose nicotine treatment, even with concomitant smoking, caused no short-term adverse effects on the cardiovascular system. Clinical Pharmacology & Therapeutics (1998) 64, 87–95; doi

Simplified pharmacokinetic methods have been used to estimate caffeine clearance in subjects with liver disease. There is a need to have a reliable, easy to implement method for research and possible clinical use. This study evaluates the use of Bayesian pharmacokinetic forecasting techniques to estimate caffeine clearance and compares its performance to other published methods. Commonly used published methods include the two-concentration overnight salivary clearance method (Jost method) and a method that samples caffeine concentrations over a 4-hour time period (Nagel method). Both have been used in studies incorporating serial measurements of caffeine clearance to predict clinical outcomes in subjects with liver disease, but these approaches have not been proven useful. However, neither method has been formally evaluated for accuracy in estimating caffeine clearance in subjects with cirrhosis. The performance of the Jost, Nagel, and Bayesian methods was compared to a Gold Standard method that accurately measured caffeine clearance in healthy subjects and subjects with cirrhosis using an intravenous infusion of stable isotope-labeled caffeine. The Bayesian method, even when only one measured concentration of caffeine was used, was more accurate, better correlated to the Gold Standard method, and had less intraindividual variation than the two previously published methods. Before the idea of using serial measurements of caffeine clearance for clinical usefulness is rejected, a reevaluation using methods of estimating caffeine clearance that are more accurate than previous paradigms is needed.

We describe a sensitive and specific method for the measurement of buprenorphine in human plasma. The method involves a structural analog as an internal calibrator, careful control of pH during sample extraction to maximize drug recovery, and back-extraction into acid followed by reextraction to eliminate endogenous interferences. After evaporation, sample residues are derivatized with heptafluorobutyric anhydride and analyzed by separation on a fused-silica polymethylsiloxane capillary column and electron-capture detection. Calibration curves were linear in the ranges 0.1–2.0 μg/L and 2.0–20 μg/L, with within-run CVs of 9.7% at 0.1 μg/L to 5.0% at 20 μg/L, and total CVs of 15.9% at 0.1 μg/L to 6.5% at 10 μg/L. The limit of quantification was 0.1 μg/L. The method was utilized in studies to determine the absolute bioavailability of sublingual doses of 2 mg of buprenorphine in 1 mL of 300 mL/L ethanol and the bioequivalence of sublingual 8-mg tablet and 300 mL/L ethanol solution formulations.

Buprenorphine administered sublingually is a promising treatment for opiate dependence. Utilizing a new, sensitive, and specific gas chromatographic electron-capture detector assay, the absolute bioavailability of sublingual buprenorphine was determined in six healthy volunteers by comparing plasma concentrations after 3- and 5-minute exposures to 2 mg sublingual and 1 mg intravenous buprenorphine. The amount of unabsorbed buprenorphine in saliva was measured after 2-, 4-, and 10-minute exposures to 2 mg sublingual buprenorphine in 12 participants. Pharmacokinetic parameters were analyzed by analysis of variance; bioequivalence was evaluated by the Schuirmann two-sided test. The 3- and 5-minute sublingual exposures each allowed 29 +/- 10% bioavailability (area under the plasma concentration-time curve unextrapolated) and were bioequivalent. Buprenorphine recovered from saliva after 2-, 4-, and 10-minute exposures was, on average, 52% to 55% of dose. Increased saliva pH was correlated with decreased recovery from saliva. Study results indicate that bioavailability of sublingual buprenorphine is approximately 30%. Sublingual exposure times between 3 and 5 minutes produce equivalent results. Buprenorphine remaining in saliva causes an almost twofold overestimation of bioavailability.

That CYP2D6 activity is an important determinant of nicotine metabolism and that people who have abnormal CYP2D6 genes are poor metabolizers of nicotine has been reported in the medical literature. The aim of this study was to assess the role of CYP2D6 in nicotine metabolism. Specifically, we compared the clearance of stable isotope-labelled nicotine and cotinine in 11 poor and 33 extensive metabolizers of dextromethorphan, a probe for CYP2D6 activity. The groups were matched by gender, age and ethnicity. Nicotine and cotinine kinetics were quite similar for cases and controls. These data suggest that CYP2D6 is not a major isozyme for the metabolism of nicotine or cotinine.

Caffeine is metabolized extensively (on average 80%) to paraxanthine. With regular caffeine consumption, average serum levels of paraxanthine are two thirds those of caffeine. Both caffeine and paraxanthine competitively and nonselectively inhibit adenosine receptors in vitro. To examine the contribution of paraxanthine to the pharmacologic activity of caffeine, we administered to 12 subjects in a crossover design oral caffeine (2 or 4 mg/kg) versus placebo or oral paraxanthine (same dose as caffeine) versus placebo, each after 3 days of methylxanthine abstinence. Both caffeine and paraxanthine significantly increased diastolic blood pressure, plasma epinephrine levels, and free fatty acids. Caffeine and paraxanthine produced a similar magnitude of response at 4 mg/kg; however, caffeine appeared to produce greater responses than paraxanthine at 2 mg/kg. Caffeine and paraxanthine have similar sympathomimetic actions. The activity of paraxanthine needs to be considered in understanding the clinical pharmacology of caffeine, particularly with chronic, repetitive caffeine consumption.

In most people, nicotine is extensively (70% to 80%) metabolized to cotinine by C-oxidation. In a clinical trial, a 57-year-old woman was found to have the expected plasma levels of nicotine but unusually low plasma levels of cotinine both when smoking cigarettes and while receiving transdermal nicotine. To characterize her metabolism, simultaneous infusions of deuterium-labeled nicotine (d2) and cotinine (d4) were administered, with comparison to 20 other control smokers. The clearance of nicotine was unusually low (6.5 ml/min/kg versus 17.2 ml/min/kg), and the half-life of nicotine significantly longer (348 minutes versus 138 minutes) in the index case subject compared with the control subjects. The clearance of cotinine was normal. The index case subject converted only 9% of nicotine to cotinine, compared with 72% for the control subjects. As far as we know, this is the first person with deficient C-oxidation of nicotine to be characterized. Deficient C-oxidation of nicotine is associated with a long half-life of nicotine and deficient generation of cotinine, both of which could influence the risks and addictiveness of tobacco use in affected individuals.

Objective Methamphetamine and ethanol are commonly used together. We examined the effects of intravenous methamphetamine (30 mg), oral ethanol (1 gm/kg), and the combination of methamphetamine (30 mg) and ethanol (1 gm/kg). Methods Eight methamphetamine and ethanol users were studied in a double-blind, double-placebo, within-subject, balanced Latin-square design. Ethanol was administered in six drinks over 30 minutes. Methamphetamine was injected 60 minutes after the first drink was begun. Cardiovascular, subjective, and neuropsychologic effects of the drug combinations were measured for 6 hours. Methamphetamine and amphetamine in plasma and urine were measured by capillary gas chromatography for 48 hours. Data were analyzed by repeated-measures ANOVA. Results Compared with methamphetamine alone, the combination increased heart rate but decreased systolic blood pressure. The net cardiovascular effect was an increase in rate pressure product, an index of cardiac work and myocardial oxygen consumption. The combination diminished the subjective effects of ethanol while not affecting the subjective effects of methamphetamine. Methamphetamine pharmacokinetics were not altered by the concurrent administration of ethanol, with the exception of lowering the apparent volume of distribution at steady state for methamphetamine. Conclusions As a potent sympathomimetic drug with α-agonist-like effects, methamphetamine increased systolic blood pressure, with minimal change in heart rate. The concurrent administration of methamphetamine and ethanol increased cardiac work, which could produce more adverse cardiovascular effects than either drug taken alone. The increased perceived global intoxication may explain the popularity of this drug combination. Clinical Pharmacology & Therapeutics (1995) 57, 559–568; doi

Cigarette smokers on average weigh less than nonsmokers. However, among smokers, those who smoke the most weigh the most. To better understand the effects of nicotine on body weight, we investigated the pharmacodynamics of intravenous nicotine and cigarette smoking in low-level smokers (10 or fewer cigarettes per day) and high-level smokers (15 to 30 cigarettes per day). Cigarette smoking and intravenous nicotine increased heart rate and energy expenditure in most smokers. The effects of intravenous nicotine and smoking were of similar magnitude, confirming that the effects of smoking are mediated by nicotine. Nicotine produced a slightly greater increase in heart rate in low-level versus high-level smokers, but energy expenditure increased to a much greater extent in low-level versus high-level smokers. The plots of plasma nicotine concentration versus responses suggest development of acute tolerance to both heart rate acceleration and increased energy expenditure in low-level smokers; high-level smokers show a similar pattern of tolerance for heart rate but show only a brief increase in energy expenditure and a hysteresis curve consistent with either rapid development of tolerance or no effect. Thus there is evidence of differential development or rate of loss of tolerance to cardiovascular versus metabolic effects of nicotine in low-level versus high-level smokers. Pharmacodynamic differences between low-level and high-level smokers may explain, at least in part, the unusual relationship between cigarette consumption and body weight.

Recently, we have shown a significantly lower excretion of α-hydroxylation products of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in the urine of rats co-administered a 500-fold higher dose of nicotine (Richter et al., Naunyn Schmiedebergs Arch Pharmacol 348:R167, 1993). In order to simulate the condition in smokers, the effect of nicotine and cotinine on the metabolism of NNK was studied at low chronic doses of [5-3H]-NNK (4.2 nmol/kg/day) administered simultaneously with 6000-fold higher doses of the tobacco alkaloids (26 µmol/kg/day). The compounds were administered subcutaneously to male F344 rats weighing about 200 g for 28 days using Alzet minipumps. Total 3H in urine and faeces was determined daily. The metabolites in urine wem analysed by HPLC. The concentration of free and bound 3H in blood was determined at the end of the study. Excretion of total 3H reached a plateau within one week. After 28 days, the rats in all groups excreted about 77% of the cumulative dose, 65% in urine and 12% in faeces, respectively. The metabolite pattern in urine did not change over time. Co-administration of nicotine and cotinine did not decrease the urinary excretion of NNK α-hydroxylation products which accounted for 61.7±0.7%, 65.2±0.4% and 66.0±0.6% of total 3H in the urine of control, nicotine- and cotinine-treated rats, respectively. The excretion of N-oxidation products accounted for 32–34% of total 3H in the urine of all rats. However, hemoglobin binding of 3H was significantly reduced from 16.3±2.1 pmol/g hemoglobin in control rats to 9.0±2.2 and 9.3±1.4 pmol/g in nicotine- and cotinine-treated rats, respectively, while the concentration of 3H in plasma (0.5–0.6 pmol/ml) was not significantly affected by the tobacco alkaloids.

Published research suggests that smokers metabolize nicotine and its major metabolite cotinine more rapidly than nonsmokers. To evaluate this possibility, we studied the disposition pharmacokinetics of intravenous deuterium-labeled nicotine in 11 smokers (administered 2.0 and 0.5 µg/kg/min × 30 minutes) and in 11 nonsmokers (0.5 µg/kg/min). Smokers did not metabolize nicotine more rapidly; the clearance of nicotine normalized for body weight was significantly slower in smokers than in nonsmokers. Cotinine elimination rates were similar in the two groups. The disposition pharmacokinetics of nicotine was similar for the low and high doses in the smokers, indicating that metabolism is dose-independent. Our findings argue against “metabolic tolerance” as a mechanism for the dose escalation observed in smokers after initiation of smoking. Our findings suggest that nicotine and cotinine kinetic parameters for smokers may be extrapolated to nonsmokers for estimating exposures to environmental tobacco smoke in nonsmokers. Clinical Pharmacology and Therapeutics (1993) 53, 316–323; doi:10.1038/clpt.1993.27

For most drugs delivered by the transdermal route, percutaneous absorption is limited by the rate of release of the drug from the device or by diffusion across the stratum corneum. However, systemic absorption also requires that the drug be taken up by dermal blood vessels. As part of a bioavailability study of a transdermal delivery system, we observed that a concomitant intravenous infusion of nicotine had a marked effect on the absorption kinetics of transdermal nicotine. Plasma concentrations of nicotine rose less rapidly, reached a lower peak, and peaked at a later time, indicating delayed absorption of transdermal nicotine after intravenous nicotine versus after transdermal nicotine administered alone. Nicotine is known to produce cutaneous vasoconstriction. The likely explanation for our observation is that intravenous nicotine constricts dermal blood vessels, thereby limiting percutaneous absorption. Other vasoconstrictor drugs would be expected to retard the absorption of transdermal nicotine and perhaps other transdermal drugs as well.

Liver microsomes from humans catalyze the NADPH-dependent oxidation of (S)-nicotine. The principal product is the 5'-carbon atom oxidation product, nicotine delta 1',5'-iminium ion, which is efficiently converted to the gamma-lactam derivative cotinine in the presence of aldehyde oxidase. Another major product is nicotine N'-oxide. In contrast to previous reports describing in vitro or in vivo studies, formation of only trans-nicotine N'-oxide was observed. Demethylation of nicotine was not observed. Studies on the biochemical mechanism of nicotine 5-carbon atom oxidation strongly implicate one major cytochrome P-450 isoenzyme (i.e., P-450 2A6) as largely responsible for delta 1',5'-iminium ion formation. Stereoselective formation of trans-nicotine N'-oxide may be catalyzed in large part by the flavin-containing monooxygenase (form II). These conclusions are based on the effects of alternate substrates for the flavin-containing monooxygenase, heat inactivation studies, immunoblot studies, and selective substrates for cytochromes P-450. The results suggest that (S)-nicotine trans N'-oxygenation and delta 1',5'-iminium ion formation may be selective probes of human liver flavin-containing monooxygenase form II and cytochrome P-450 2A6 activities, respectively, useful for in vivo phenotyping of humans.

A stable isotope-labeled drug method was used to determine the absolute bioavailability and absorption kinetics of a transdermal nicotine-delivery system (TTS). TTSs are being developed as an adjunct to smoking-cessation therapy. Deuterium-labeled nicotine was infused for 24 hours simultaneously to TTS application in cigarette-abstinent smokers. In 11 subjects with good patch adhesion, an average systemic dose of 19 mg nicotine was delivered, with average absolute bioavailability of 82%. The rate of nicotine absorption was maximal between 6 and 12 hours after TTS application and declined thereafter, plateauing between 16 and 24 hours at 62% of the maximal rate. Ten percent of nicotine was absorbed after the TTS was removed, demonstrating a reservoir for nicotine in the skin. Our study demonstrates the applicability of stable isotope methods in understanding the clinical pharmacology of transdermal drugs. Clinical Pharmacology and Therapeutics (1991) 50, 286–293; doi:10.1038/clpt.1991.138

The stable isotope-labeled compound 3',3'-dideuteronicotine was used to investigate the disposition kinetics of nicotine in smokers, the systemic absorption of nicotine from cigarette smoke, and the bioavailability of nicotine ingested as oral capsules. Blood levels of labeled nicotine could be measured for 9 hours after a 30-minute intravenous infusion. Analysis of disposition kinetics in 10 healthy men revealed a multiexponential decline after the end of an infusion, with an elimination half-life averaging 203 minutes. This half-life was longer than that previously reported, indicating the presence of a shallow elimination phase. Plasma clearance averaged 14.6 ml/min/kg. The average intake of nicotine per cigarette was 2.29 mg. A cigarette smoke-monitoring system that directly measured particulate matter in smoke was evaluated in these subjects. Total particulate matter, number of puffs on the cigarette, total puff volume, and time of puffing correlated with the intake of nicotine from smoking. The oral bioavailability of nicotine averaged 44%. This bioavailability is higher than expected based on the systemic clearance of nicotine and suggests that there may be significant extrahepatic metabolism of nicotine.

[ Abstract A method uslng combined gas chromatography/mass spectrometry (GC/MS) for determination of the cocaine pyrolysis product anhydroecgonine methyl ester (AEME) in urine is described. Ustng this method, we found that human subjects who smoked coca|ne under laboratory conditions excreted substantial amounts of AEME in thelr urine. Little, if any, AEME was excreted in the urine when the same subjects were admlnistered coca ine by intravenous and Jntranasal routes. AEME may b~~a useful marker for coca]ne (crack) smoking. The pharmac~logy of AEME is unknown. The possibility that AEME may play a role in the effects associated with cocaine smoking needs to be examined.

Some recent epidemiologic studies have reported a nonlinear dose-response in the relationship between coffee consumption and health risks, such that the risks increase disproportionately to the increase in dose. Assuming caffeine contributes to the adverse health effects of coffee, a possible explanation for the nonlinear dose-response relationship is dose-dependent metabolism of caffeine. We examined the hypothesis that under chronic dosing conditions the metabolism of caffeine is dose-dependent. Nine healthy subjects were given, in randomized 5-day treatment blocks, placebo, 4.2 (low) and 12 (high) mg/kg/day caffeine in decaffeinated coffee, in six divided doses spaced throughout the day. On the third day of each dosing period, 25 mg of stable-isotope labeled caffeine (2-13C, 1,3-15N2) was given intravenously. Clearance of labeled caffeine fell from 0.118 (placebo treatment) to 0.069 (low dose; p less than 0.005) and to 0.54 (high dose; p less than 0.001) L/hr/kg. The formation and metabolite clearances of paraxanthine, the major primary metabolite of caffeine, also decreased comparing the low and high doses (p less than 0.05). We conclude that caffeine metabolism is dose-dependent, resulting in nonlinear accumulation of methylxanthines in the body. Dose-dependent metabolism of caffeine may explain in part why people who drink large amounts of coffee are at greater risk for cardiovascular disease.

A method for the synthesis of (3'R,5'S-trans-3'-hydroxycotinine, a major metabolite of nicotine in humans, is described. The method involves deprotonation of (S)-cotinine with lithium diisopropylamide (LDA) followed by oxidation with the transition metal peroxide oxodiperoxymolybdenum(pyridine)(hexamethylphosphoric triamide) (MoOPH) to give an 80:20 mixture of trans-/cis-3'-hydroxycotinine. The pure (greater than 98%) trans isomer is obtained by conversion to the solid hexanoate ester, recrystallization, and cleavage of the ester by heating with n-butylamine. GC-MS analysis of urine extracts from several smokers indicated that in humans metabolic 3'-hydroxycotinine is 95-98% trans.

A sensitive gas chromatographic assay has been developed to measure concentrations of nornicotine in human urine. A structural analogue, 5-methylnornicotine, is used as an internal standard. Both nornicotine and the internal standard were converted to the corresponding N′-propyl derivatives using a novel reductive alkylation procedure. The N′-propyl derivatives have good chromatographic properties, which allows quantitative measurement in the low nanograms per milliliter range. Concentrations of nornicotine in smokers' urine were quantitated and compared with the concentrations of nicotine and its metabolites, cotinine, nicotine-N-oxide and cotinine-N-oxide.

Background Ephedra-free weight loss dietary supplements (DS) containing Citrus aurantium (CA), a botanical source of the adrenergic amines synephrine (SYN) and octopamine, have rapidly replaced banned ephedra products, but have not been adequately studied. These DS may have some of the health risks associated with ephedra. We present novel data on CA PK/PD in humans. Methods In a randomized, double blind, placebo-controlled crossover study, 10 healthy adults took 1 oral dose of CA alone (Advantra Z®, (ADV) with 45 mg SYN), and a multi-component DS (Xenadrine EFX® (XEN) with 5.5 mg SYN), with a 1-week washout between treatments. Plasma drug levels were measured over 12 hours by LC-MS/MS. Results XEN but not ADV increased systolic and diastolic BP with peak changes over placebo at 2 hrs of 9.6 ± 6.2 mm Hg systolic (p=0.047), and 9.1 ± 7.8 mm Hg diastolic (p=0.002). Heart rate was increased at 6 hrs (16.7 bpm with XEN, p=0.011; 11.4 bpm with ADV, p=0.031). SYN Cmax was 2.8 ng/ml with ADV and 0.35 ng/ml with XEN. Caffeine Cmax was 5.1 mcg/ml with XEN. Plasma levels of octopamine were negligible. Dose-adjusted SYN PK were similar between treatments with tmax= 90 min, t1/2= 3.0 hrs, V/F= 16347 L, and CL/F= 88.9 L/min for XEN. Conclusions Ephedra-free weight loss DS have significant cardiovascular stimulant actions. These pressor effects are not likely caused by CA, since a 8-fold higher dose of synephrine (ADV) had no effect on blood pressure, but may be attributable to caffeine and other stimulants in the DS. Clinical Pharmacology & Therapeutics (2005) 77, P5–P5; doi: 10.1016/j.clpt.2004.11.022

Background/Aims To examine genetic factors that influence sensitivity to nicotine (Nic) in never smokers. Methods 20 Caucasian and 20 Asian never smokers received 7 mg nicotine skin patches, with frequent blood levels, subjective and cardiovascular (CV) effect monitoring. CYP2A6, the enzyme primarily responsible for Nic metabolism, was genotyped. Results 25 subjects had wild type alleles (*1A and/or*1B) for CYP2A6, while 15 subjects had CYP2A6 variant alleles (*4,*9,*10) which are associated with slower Nic metabolism (Var-2A6). 8 subjects vomited, of whom 75% had Var-2A6 compared to 25% in those who did not (p

Background/Aims Methamphetamine has a chiral structure. The aim of the present study was to assess the pharmacokinetics of methamphetamine enantiomers in humans. Methods In a randomized, double-blind, six-period crossover study, methamphetamine (0.25 mg/kg d- or l-, 0.5 mg/kg d-, l- or racemic (1:1) methamphetamine and placebo) was given intravenously to 12 healthy methamphetamine users. Results d-Methamphetamine showed 30% smaller AUC compared to l-methamphetamine after administration of the racemic form. However, AUCs were similar between d- and l-methamphetamine when given on separate occasions at both doses (0.25 and 0.5 mg/kg). AUC ratios for d-methamphetamine/l-methamphetamine were 0.910 (90% CI; 0.837–0.984) for the 0.25 mg/kg dose, 0.894 (0.821–0.967) for the 0.5 mg/kg dose, and 0.679 (0.623–0.736) for the racemic dose. AUC and Cmax at 0.5 mg/kg dose were twofold greater than those at 0.25 mg/kg dose for both enantiomers. The elimination half-lives were slightly longer for l-methamphetamine. Vd was similar for both formulations. AUC ratios for amphetamine/methamphetamine were significantly higher for the d-enantiomer (16–17%) than the l-enantiomer (3–4%). Conclusions d- and l-Methamphetamine are apparently bioequivalent in terms of AUC when given separately, with linear pharmacokinetics between 0.25 and 0.5 mg/kg doses. However, administration of d-methamphetamine results in a higher metabolite concentration compared to the l-form. NIDA DA12521 and DA12393. Clinical Pharmacology & Therapeutics (2005) 77, P37–P37; doi: 10.1016/j.clpt.2004.12.034

CYP2A6 is the primary enzyme catalyzing the metabolism of nicotine (NIC) and its proximate metabolite cotinine (COT). Pregnancy accelerates NIC and COT metabolism, suggesting that CYP2A6 activity is modulated by sex hormones. We hypothesize that sex hormones administered as oral contraceptives (OC) also induce CYP2A6 activity. Two hundred ninety healthy participants in a twin study of the genetics of NIC metabolism received IV infusions of deuterium-labeled NIC and COT, with blood sampling to determine disposition kinetics. Women taking OC had substantially faster clearance (CL) of NIC and COT, and CL or NIC via the COT pathway, the latter an indicator of CYP2A6 activity, compared to women not taking OC or compared to men. CL values were also significantly higher in women not taking OC compared to men. (See Table) These findings indicate that OC use accelerates the metabolism of NIC and COT and suggests induction of CYP2A6 activity. This is in contrast to most other reports of OCs inhibiting oxidative metabolism. Insofar as smokers smoke to obtain desired levels of nicotine in the body, OC use might influence cigarette consumption. Clinical Pharmacology & Therapeutics (2004) 75, P36–P36; doi: 10.1016/j.clpt.2003.11.135 Table 1. Women on OC Women no OC Men * Different than women not taking OC and men; † different than men; both p

Context.—Racial differences in tobacco-related diseases are not fully explained by cigarette-smoking behavior. Despite smoking fewer cigarettes per day, blacks have higher levels of serum cotinine, the proximate metabolite of nicotine.Objective.—To compare the rates of metabolism and the daily intake of nicotine in black smokers and white smokers.Design.—Participants received simultaneous infusions of deuterium-labeled nicotine and cotinine. Urine was collected for determination of total clearance of nicotine and cotinine, fractional conversion of nicotine to cotinine, and cotinine elimination rate. Using cotinine levels during ad libitum smoking and clearance data, the daily intake of nicotine from smoking was estimated.Setting.—Metabolic ward of a university-affiliated public hospital.Participants.—A total of 40 black and 39 white smokers, average consumption of 14 and 14.7 cigarettes per day, respectively, of similar age (mean, 32.5 and 32.3 years, respectively) and body weight (mean, 73.3 and 68.8 kg, respectively).Main Outcome Measures.—Clearance (renal and nonrenal), half-life, and volume of distribution of nicotine and cotinine and the calculated daily intake of nicotine.Results.—The total and nonrenal clearances of nicotine were not significantly different, respectively, in blacks (17.7 and 17.2 mL·min−1·kg−1) compared with whites (19.6 and 18.9 mL·min−1·kg−1) (P=.11 and .20). However, the total and nonrenal clearances of cotinine were significantly lower, respectively, in blacks (0.56 and 0.47 mL·min−1·kg−1) than in whites (0.68 vs 0.61 mL·min−1·kg−1; P =.009 for each comparison). The nicotine intake per cigarette was 30% greater in blacks compared with whites (1.41 vs 1.09 mg per cigarette, respectively; P =.02). Volume of distribution did not differ for the 2 groups, but cotinine half-life was higher in blacks than in whites (1064 vs 950 minutes, respectively; P =.07).Conclusions.—Higher levels of cotinine per cigarette smoked by blacks compared with whites can be explained by both slower clearance of cotinine and higher intake of nicotine per cigarette in blacks. Greater nicotine and therefore greater tobacco smoke intake per cigarette could, in part, explain some of the ethnic differences in smoking-related disease risks.

Cocaine abuse is a common clinical problem among opioid-dependent patients who are in methadone maintenance treatment. In an open prospective study, 16 DSM-III-R, cocaine-dependent, methadone maintenance treatment patients were treated with fluoxetine, at a mean dose of 45 mg/day for 9 weeks. Eleven subjects (69%) were infected with the human immunodeficiency virus. Cocaine use was significantly reduced by the end of treatment, although most subjects did not achieve abstinence. Comparison of intake to week 9 showed a significant decrease in self-reported cocaine use, craving, and quality of high. Actual cocaine use was measured by a quantitative analysis of cocaine and benzoylecgonine (BE) concentrations in plasma and urine. Median BE and cocaine concentrations in urine decreased significantly from intake to week 9 of fluoxetine treatment. This decrease would not have been detected if BE had been measured only qualitatively, as present or absent in the urine. Fluoxetine was well tolerated in combination with methadone and did not appear to alter methadone concentrations in plasma. Few adverse effects were noted. No subjects had to discontinue fluoxetine. Fluoxetine may be a promising treatment approach for cocaine abuse in methadone maintenance patients. Quantitative determination of exact cocaine and BE concentrations in biofluids may be a more accurate method of measuring cocaine use outcome than qualitative urinalysis.

To the Editor: The recent article by Kyerematen et al.1 provides some new and interesting data on the nature of nicotine metabolism in humans. Of particular interest is their observation of a new metabolite, “demethyl-cotinine-2\2'-enamine.

We studied the bioavailability and disposition kinetics of pethidine and pentazocine in patients with alcoholic cirrhosis and age-matched healthy subjects. In the presence of liver disease, the bioavailability of pethidine was 31% and pentazocine 233% greater than in normals. Systemic clearance was approximately half and terminal half-life double normal for both drugs, whereas volumes of distribution were unchanged. Because of greater bioavailability, oral doses of pethidine and pentazocine should be reduced substantially in patients with cirrhosis. When multiple oral or parenteral doses are required, dosing interval should be lengthened or repeated doses reduced below initial doses because of lower systemic clearance.

To estimate daily nicotine consumption from the smoking of cigarettes delivering different amounts of nicotine, we studied 12 healthy subjects who smoked 30 cigarettes a day of their usual brand (x = 1.2 mg nicotine) or high- (2.5 mg) or low-nicotine (0.4 mg) research cigarettes. Blood nicotine and carboxyhemoglobin concentrations were measured every 2 hr. Nicotine consumption was estimated by the 24-hr area under the blood concentration-time curve (AUC) and compared across smoking conditions. There was considerable interindividual variation in the nicotine AUC among subjects smoking research cigarettes or while smoking usual brands, even when the latter were normalized on the basis of machine-predicted nicotine delivery. Most subjects smoked the high-nicotine research cigarettes less intensively so that nicotine levels were only modestly higher after smoking high-nicotine cigarettes than after usual brands. Low-nicotine research cigarettes were not smoked more intensively than usual brands and blood nicotine levels were substantially lower than those after smoking a usual brand. Nicotine consumption while smoking usual brands correlated strongly with consumption while smoking high- (r = 0.91) and low-nicotine (r = 0.85) research cigarettes. Circadian studies of blood concentration of nicotine while smoking cigarettes provided a direct estimate of the level of nicotine in the body throughout the day. Results confirm observations by others that levels of nicotine in the body vary widely among individuals even when smoking the same number of identical cigarettes. Thus, neither number of cigarettes smoked nor smoking-machine delivery predict daily nicotine exposure very well. Clinical Pharmacology and Therapeutics (1982) 32, 758–764; doi:10.1038/clpt.1982.233

We describe methods for the synthesis of enantiomerically pure (S)-nicotine-3′,3′-d2. (S)-nornicotine-3′,3′-d2, and (S)-cotinine-4′,4′-d2. The key intermediate was 5-bromomyosmine, which underwent base catalyzed exchange with deuterium oxide to give 5-bromomyosmine-3′,3′-d2 with > 99% incorporation of label. This intermediate was reduced to (±)-5-bromonornicotine-3′,3′-d2 with sodium borohydride, resolved, and converted to (S)-nornicotine-3′,3′-d2 by reductive debromination with hydrogen and a palladium catalyst. Reductive alkylation with formaldehyde and sodium borohydride provided (S)-nicotine-3′,3′-d2. which was converted to (S)-cotinine-4′,4′-d2 by reaction with bromine followed by zinc reduction. The deuterium label is located at positions that are not attacked in the major routes of mammalian metabolism of these alkaloids. Syntheses of tetradeuterated analogs of nicotine and cotinine and a pentadeuterated analog of nicotine, in which additional deuterium atoms are incorporated in the methyl groups, are also reported.

Regiospecific syntheses of the three monomethylthio analogues of 1-(2,4,5-trimethoxyphenyl)-2-aminopropane are described. The three isomeric amines were evaluated for potential psychotomimetic potency using the rabbit hyperthermia assay. Enantiomeric compositions and time-concentration curves in rat brains were determined following intraperitoneal administration of each compound. The biological data are contrasted with the corresponding results obtained with the potent human psychotogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM).

The synthesis of high specific activity tritium labeled (S)-nicotine and (S)-cotinine has been achieved. (S)-5-Bromonornicotine of high enantiomeric purity was converted to the corresponding (S)-5-bromonicotine by reductive amination with formaldehyde and sodium borohydride. Tritiolysis of this intermediate with carrier free tritium in the presence of triethylamine using 10% Pd/C catalyst provided (S)-nicotine-5- H with a specific activity of 32 Ci/mmol in ethanol solvent and 28 Ci/mmol in tetrahydrofuran solvent. Similarly, tritiation of (S)-5-bromocotinine, obtained by oxidation of (S)-5-bromocotinine, obtained by oxidation of (S)-5-bromonicotine with bromine followed by reduction of the intermediate (S)-3′, 3′, 5-tribromonicotine with zinc dust, yielded the corresponding (S)-cotinine-5- H (22.8 Ci/mmol). All reactions proceeded in good to excellent yields.

Diphenylborane, prepared in situ by the reaction of methyl diphenylborinate with lithium aluminum hydride, reacts readily with olefins to provide the corresponding alkyldiphenylboranes. Diphenylborane generated by the reaction of boron trifluoride etherate with pyridinediphenylborane likewise reacts with olefins to give alkyldiphenylboranes. The latter method is suitable for the hydroboration of olefins containing functional groups. Alkyldiphenylboranes react with methyl vinyl ketone affording good to excellent yields of the corresponding 4-alkyl-2-butanones. The advantages for the use of alkyldiphenylboranes in the conjugate addition reactions of organoboranes are discussed.