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Objective To help predict the consequences of precursor regulation, we compared the pharmacokinetics and pharmacodynamics of the methamphetamine (INN, metamfetamine) stereoisomers. Methods In this study 12 methamphetamine abusers received intravenous d-methamphetamine (0.25 and 0.5 mg/kg), l-methamphetamine (0.25 and 0.5 mg/kg), racemic methamphetamine (0.5 mg/kg), or placebo with the use of a 6-session, double-blind, placebo-controlled, balanced crossover design. Pharmacokinetic measures (including area under the plasma concentration-time curve [AUC], elimination half-life, systemic clearance, apparent volume of distribution during the elimination phase, and apparent bioavailability) and pharmacodynamic measures (including heart rate, blood pressure, respiratory rate, and visual analog scale ratings for “intoxication,” “good drug effect,” and “drug liking”) were obtained. Results Pharmacokinetic parameters for the individual enantiomers given separately were similar, with dose-proportional increases in AUC and maximum plasma concentration. After racemate administration, the AUC for d-methamphetamine was 30% smaller than that for l-methamphetamine (P = .0085). The elimination half-lives were longer for l-methamphetamine (13.3–15.0 hours) than for d-methamphetamine (10.2–10.7 hours) (P < .0001). Compared with placebo, d-methamphetamine (0.25 mg/kg, 0.5 mg/kg, and racemic) increased the heart rate (P < .0001), blood pressure (P < .0001), and respiratory rate (P < .05), and this increase lasted for 6 hours. The peak heart rate changes after racemic methamphetamine and 0.5 mg/kg d- and l-methamphetamine were similar (18.7 ± 23.4 beats/min, 13.5 ± 18.5 beats/min, and 10.7 ± 10.2 beats/min, respectively), but racemic methamphetamine and 0.5 mg/kg d-methamphetamine increased systolic blood pressure more than 0.5 mg/kg l-methamphetamine (33.4 ± 17.8 beats/min and 34.5 ± 18.9 beats/min, respectively, versus 19.5 ± 11.3 beats/min; P < .01). l-Methamphetamine, 0.5 mg/kg, was psychoactive, producing peak intoxication (46.0 ± 35.3 versus 30.3 ± 24.9) and drug liking (47.7 ± 35.1 versus 28.6 ± 24.8) ratings similar to 0.5 mg/kg d-methamphetamine, but the effects of l-methamphetamine dissipated more quickly (approximately 3 hours versus 6 hours). The effects of 0.25 mg/kg l-methamphetamine were similar to those of placebo. Racemic methamphetamine was similar to d-methamphetamine with regard to most pharmacodynamic measures. Conclusion The pharmacokinetics of the methamphetamine enantiomers are similar, but there are substantial pharmacodynamic differences between the isomers. At high doses, l-methamphetamine intoxication is similar to that of d-methamphetamine, but the psychodynamic effects are shorter-lived and less desired by abusers. Racemic and d-methamphetamine have similar effects and would be expected to have comparable abuse liabilities. Clinical Pharmacology & Therapeutics (2006) 80, 403–420; doi: 10.1016/j.clpt.2006.06.013

Background Patients in harm-reduction treatment programs are switching from intravenous to other routes of methamphetamine (INN, metamfetamine) administration to avoid risks associated with needle use. Relatively little has been reported about the bioavailability of methamphetamine when smoked or used intranasally. Methods Eight experienced methamphetamine users were administered smoked or intranasal methamphetamine concurrently with an intravenous dose of deuterium-labeled methamphetamine. Plasma and urine concentrations were measured for calculation of bioavailability and other pharmacokinetic parameters by noncompartmental methods. Results Methamphetamine was well absorbed after smoking or intranasal administration, with bioavailabilities of 79% after intranasal administration and 67% of the estimated delivered dose or 37.4% of the absolute (pipe) dose after smoking. Maximum methamphetamine concentrations occurred at 2.7 and 2.5 hours after intranasal and smoked doses. The elimination half-life was similar for intravenous (11.4 hours), intranasal (10.7 hours), and smoked (10.7 hours) methamphetamine. Clearance (272 mL x h(-1) x kg(-1)), steady-state volume of distribution (4.2 L/kg), and mean residence time (16 hours) of the intravenous dose were similar to previously reported values. Dextroamphetamine (INN, dexamfetamine) half-life (all routes) was 16.2 hours. Methamphetamine and dextroamphetamine renal clearances (all routes) were about 100 and 1100 mL x h(-1) x kg(-1), respectively. Conclusions Intranasal and smoked methamphetamine are well absorbed. Although intranasal or smoked routes may decrease the risk of transmission of blood-borne diseases, exposure to methamphetamine and the possibility of drug-related complications remain substantial.

We describe the syntheses of benzoylecgonine (1,1,1- 2 H 3 )methyl ester [( 2 H 3 ) cocaine], ( 2 H 5 )benzoylecgonine, ( 2 H 5 )benzoylecgonine methyl ester [( 2 H 5 )cocaine], benzoylecgonine (2,2,2- 2 H 3 )ethyl ester [( 2 H 3 )cocaethylene], ( 2 H 5 )benzoylecgonine ethyl ester [( 2 H 5 )cocaethylene], ( 2 H 5 )benzoylecgonine (2,2,2- 2 H 3 )ethyl ester [( 2 H 8 )cocaethylene], ecgonine (1,1,1- 2 H 3 )methyl ester, ecgonine (2,2,2- 2 H 3 )ethyl ester, ecgonine (1,1,2,2,2- 2 H 5 )ethyl ester and anhydroecgonine (1,1,1- 2 H 3 )methyl ester. ( 2 H 5 )Cocaine and ( 2 H 3 )cocaethylene have been administered to human subjects to study the interactions of cocaine and ethanol. The other eight compounds were utilized as analytical standards or internal standards for GC-MS quantitation of cocaine and its metabolites in biological fluids.

A gas chromatographic method for the determination of levorphanol in human plasma is described. The method utilizes extractive alkylation with tetrabutylammonium cation as the phase-transfer catalyst and pentafluorobenzyl bromide as the alkylating agent, and employs a structural analog, d-3-hydroxy-N-ethylmorphinan, as the internal standard. The pentafluorobenzyl ethers formed are separated by capillary gas chromatography and detected by electron capture. The method has good precision and accuracy for concentrations ranging from 0.25 ng/ml to 100 ng/ml and has been used to measure plasma concentrations as part of a study to evaluate the management of chronic neuropathic pain with levorphanol.

Buprenorphine is an effective new treatment for opiate dependence. This study compared the bioavailability of buprenorphine from a tablet to that from a reference solution. Six men experienced with, but not dependent on, opiates (DSM-III-R) were each administered 7.7 mg of buprenorphine in liquid form and 8 mg in tablet form 1 week apart in a balanced crossover design. Plasma levels were measured by electron capture capillary gas chromatography (GC), and concentration-time curves were constructed. Pharmacokinetic data were analyzed by analysis of variance. The bioavailability from the tablet was approximately 50% that from the liquid and was not affected by saliva pH. Lower bioavailability from the tablet may be due to slow dissolution.

Ethanol alters the hepatic biotransformation of cocaine, resulting in transesterification to a novel active metabolite, cocaethylene. Because of first pass metabolism, oral drug administration might be expected to produce relatively larger concentrations of cocaethylene than would intravenous or smoked administration. We, therefore, compared the effects of route of cocaine administration on the formation and elimination of cocaethylene. Six experienced cocaine users were tested in 6 sessions, approximately 1 week apart. Deuterium-labeled cocaine (d₅) was administered in all conditions. Oral cocaine-d₅ 2.0 mg/kg, intravenous cocaine-d₅ 1.0 mg/kg, and smoked cocaine-d₅ (200 mg) were administered after oral ethanol 1.0 g/kg or placebo. A small, intravenous dose of deuterated cocaethylene (d₃) also was administered with all conditions for determination of cocaethylene formation. Physiologic and subjective effects were recorded and plasma cocaine-d₅, cocaethylene-d₅, cocaethylene-d₃, and benzoylecgonine-d₅ were measured by gas chromatography-mass spectrometry. About 24% (± 11) of intravenous cocaine was converted to cocaethylene. The oral route (34% ± 20) was significantly greater than from the smoked route (18% ± 11) and showed a trend toward significance for greater formation of cocaethylene compared to the intravenous route. Within each route, the cocaine-ethanol combination produced greater increases in heart rate and rate-pressure product than cocaine alone. Global intoxication effects across time after smoking or intravenous administration were significantly greater when cocaine and ethanol were both given. Administration of cocaine by different routes alters the amount of cocaethylene formed through hepatic first-pass effects. Increased cardiovascular and subjective effects might explain the toxicity and popularity of the combined drugs.

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 l-methamphetamine (l-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 l-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 l-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)]:[l-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.

Rationale Salvinorin A (SA) is a highly selective kappa opioid receptor agonist and the putative psychoactive compound in Salvia divinorum (SD), an increasingly abused hallucinogenic plant. Objectives The objectives of this study were to characterize the physiological and subjective effects of SA versus placebo and measure drug and metabolite levels. Methods Sublingual SA doses up to 4 mg were administered in dimethyl sulfoxide/polyethylene glycol 400 solution to eight SD-experienced subjects using a placebo-controlled ascending-dose design. Results No dose of SA produced significantly greater physiological or subjective effects than placebo. Furthermore, effects did not resemble reported “typical” effects of smoked SD. SA was detectable in plasma and urine, but was, in most cases, below the reliable limit of quantification (0.5 ng/mL). Conclusions Our results suggest that the sublingual bioavailability of SA is low. Higher doses, alternate formulations, or alternate routes of administration will be necessary to study the effects of SA in humans.

Polar alcohols obtained from their β-(trimethylsilyl) ethoxymethyl (SEM) ethers by deprotection using the tetra-n-butylammonium fluoride reagent, can be efficiently isolated after quantitative removal of the excess reagent as the insoluble tetra-n-butylammonium perchlorate salt. Standard extractive workup then gives the alcohols in high yield. The method is applicable to any reaction involving the use of tetra-n-butylammonium fluoride for the removal of protective groups.

Background: Concurrent use of cocaine and alcohol results in formation of a cocaine homolog and metabolite—cocaethylene. Methods: To characterize cocaethylene pharmacology, ten paid volunteer subjects were given deuterium-labeled (d 5 ) cocaine (0.3, 0.6, and 1.2 mg/kg and cocaine placebo) by a 15-min constant rate intravenous injection 1 h after a single oral dose of ethanol (1 g/kg) or ethanol and cocaine placebo using a double-blind, crossover design. Six of the same volunteers subsequently received a 1.2 mg/kg dose of cocaine alone. A small (7.5 mg) nonpharmacologically active dose of deuterium-labeled cocaethylene-d 3 was concurrently administered with the cocaine to enable calculation of absolute cocaethylene formation and clearance. Plasma and urine cocaine, cocaethylene, and benzoylecgonine concentrations, physiologic and subjective effects were measured. Results: When co-administered with ethanol, 17±6% (mean±S.D.) of the cocaine was converted to cocaethylene. Cocaethylene peak plasma concentrations and AUC increased proportionally to the cocaine dose. Ethanol ingestion prior to cocaine administration decreased urine benzoylecgonine levels by 48% and increased urinary cocaethylene and ecgonine ethyl ester levels. Subjects liked and experienced more total intoxication after the combination of cocaine and ethanol than after either drug alone. Conclusions: In the presence of ethanol, the altered biotransformation of cocaine resulted in 17% of an intravenous cocaine dose being converted to cocaethylene and relatively lower urinary concentrations of benzoylecgonine.

Recent studies have demonstrated the utility of quantitative assays for benzoylecgonine in assessing the efficacy of cocaine-dependence-treatment programs to determine if the amount of cocaine consumed has been reduced. We describe a simple gas chromatographic method for determining benzoylecgonine concentrations in urine. BZE is extracted from urine as an ion pair with tri-n-propylsulfonium ion. Injection into the heated injection port of the gas chromatograph results in thermal conversion of the ion pair to the n-propyl ester of BZE. Using the structural analogue of BZE, m-toluylecgonine, as the internal standard, the analysis is carried out on a (5% phenyl)methylpolysiloxane capillary column with nitrogen-phosphorus detection. There was a good correlation between BZE concentrations determined by gas chromatography-mass spectrometry and concentrations determined by the method described in this paper. Application to cocaine-dependence-treatment programs is discussed.

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.

THE MASS BALANCE OF BUPRENORPHINE IN HUMANS E. Everhart;Polly Cheung;John Mendelson;Robert Upton;Reese Jones; Clinical Pharmacology & Therapeutics

Synthese du compose du titre par condensation de dichloro-4,7 quinoleine et de diethylamino-5 pentylamine (obtenue a partir de l'acide glutamique)