Abstract
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.
Footnotes
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Send reprint requests to: Dr. S. Michael Owens, Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, 4301 W. Markham, Slot 611, Little Rock, AR 72205. E-mail: owenssamuelm{at}exchange.uams.edu or Dr. W. Brooks Gentry, Department of Anesthesiology, University of Arkansas for Medical Sciences, 4301 W. Markham, Slot 515, Little Rock, AR 72205. E-mail: gentrywilliamb{at}exchange.uams.edu
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↵1 This work was supported by National Institute on Drug Abuse Grants DA11560 (to S.M.O.) and DA0339 (to W.B.G.).
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↵2 Current address: Novartis Pharma AG, K 135-3-22, Klybeckstrasse, CH-4002 Basel, Switzerland.
- Abbreviations:
- (+)-METH
- (+)-methamphetamine
- (+)-AMP
- (+)-amphetamine
- AUC
- area under the concentration versus time curve from time zero to infinity
- Received September 9, 1999.
- Accepted November 13, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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