Human Pharmacology of the methamphetamine stereoisomers

• Published in: Clinical pharmacology and therapeutics 2006-10, Vol.80 (4), p.403-420
• Main Authors: Mendelson, John, Uemura, Naoto, Harris, Debra, Nath, Rajneesh P., Fernandez, Emilio, Jacob, Peyton, Everhart, E. Thomas, Jones, Reese T.
• Format: Article
• Language: English
• Subjects: Adult; Amphetamine-Related Disorders - metabolism; Area Under Curve; Biological and medical sciences; Biological Availability; Blood Pressure - drug effects; Central Nervous System Stimulants - administration & dosage; Central Nervous System Stimulants - pharmacokinetics; Central Nervous System Stimulants - pharmacology; Cross-Over Studies; Double-Blind Method; Half-Life; Heart Rate - drug effects; Humans; Injections, Intravenous; Male; Medical sciences; Methamphetamine - administration & dosage; Methamphetamine - pharmacokinetics; Methamphetamine - pharmacology; Pharmacology. Drug treatments; Research Design; Respiration - drug effects; Stereoisomerism
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1016/j.clpt.2006.06.013

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 methamph