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Vol. 292, Issue 3, 1042-1047, March 2000

Disposition of Methamphetamine and Its Metabolite Amphetamine in Brain and Other Tissues in Rats after Intravenous Administration1

Gilles J. Rivière2 , W. Brooks Gentry and S. Michael Owens

Departments of Pharmacology and Toxicology (G.J.R., W.B.G., S.M.O.) and Anesthesiology (W.B.G.), College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas

These studies characterized the concentration-time profile of (+)-methamphetamine [(+)-METH] and its metabolite (+)-amphetamine [(+)-AMP] in the brain and five other tissues after (+)-METH administration. Male Sprague-Dawley rats received a pharmacologically active (+)-METH i.v. bolus dose (1.0 mg/kg) or a nonpharmacologically active s.c. infusion (20 h at 1.2 mg/kg/day). Tissues (n = 3 per time point) were collected for more than four elimination half-lives in the i.v. group, or at a single steady-state time point (20 h) in the s.c. group. Based on data from the area under the concentration-time curves after i.v. dosing, the rank order of (+)-METH tissue accumulation was kidney > spleen > brain > liver > heart > serum with terminal elimination half-life values ranging from 53 to 66 min. (+)-METH concentrations were highest at the first measured time point (2 min) in all tissues except the spleen, which peaked at 10 min. The brain-to-serum concentration ratio rose from 7:1 at 2 min to a peak of 13:1 at 20 min before equilibrating to a constant value of 8:1 at 2 h. Following s.c. (+)-METH dosing, the (+)-METH brain-to-serum concentration ratio was the same as the equilibrated ratio following i.v. dosing. (+)-AMP concentrations peaked at 20 min in all tissues before decaying with terminal elimination half-life values ranging from 68 to 75 min. Analysis of the area under the concentration-time curve molar amounts of (+)-AMP and (+)-METH showed that (+)-AMP accounted for approximately one-third of the drug tissue exposure over time. Thus, these data indicate the importance of both (+)-METH and (+)-AMP in pharmacological effects following i.v. (+)-METH administration.

1 This work was supported by National Institute on Drug Abuse Grants DA11560 (to S.M.O.) and DA0339 (to W.B.G.).

2 Current address: Novartis Pharma AG, K 135-3-22, Klybeckstrasse, CH-4002 Basel, Switzerland.

0022-3565/00/2923-1042$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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