Vol. 288, Issue 2, 752-758, February 1999

l-Methamphetamine Pharmacokinetics and Pharmacodynamics for Assessment of In Vivo Deprenyl-Derived l-Methamphetamine¹

William P. Melega, Arthur K. Cho, Debra Schmitz, Ronald Kuczenski and David S. Segal

Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, California (W.P.M., A.K.C., D.S.); and Department of Psychiatry, UCSD School of Medicine, San Diego, California (R.K., D.S.S.)

This study evaluated whether the caudate-putamen dopamine response that has been observed after deprenyl administration could be attributed exclusively to metabolically generated l-methamphetamine (l-MeAmp). Brain and plasma levels of deprenyl and l-MeAmp were measured after deprenyl (10 mg/kg s.c.) from 10 to 60 min in conscious rats. Peak caudate-putamen levels were observed for deprenyl (15 nmol/g) at 10 min and for l-MeAmp (3 nmol/g) at 30 min. In a parallel study, l-MeAmp metabolism was evaluated. After l-MeAmp (20 mg/kg s.c.), metabolite levels remained low relative to those of the parent compound: l-amphetamine, ~5 to 12%; and para-hydroxy-l-methamphetamine (OH-MeAmp), ~0.25%. Accordingly, l-MeAmp was considered to be the primary pharmacologically active deprenyl metabolite. A pharmacokinetic-pharmacodynamic analysis was then used to relate these pharmacokinetic data to the results of previous microdialysis studies in which increases in extracellular dopamine were measured in the caudate-putamen after l-MeAmp (3-18 mg/kg) and after deprenyl (10 mg/kg). Dopamine response-area under curve versus dose plots were generated and used to show that an administered dose of 4 mg/kg l-MeAmp would be necessary to effect a dopamine response-area under curve comparable to that observed after the deprenyl dose. However, the present pharmacokinetic results indicated that l-MeAmp brain levels after deprenyl corresponded to those that would be obtained from 0.4 mg/kg l-MeAmp (i.e., one tenth of the required dose). Collectively, these results suggest that the acute increases in extracellular dopamine observed after deprenyl are not due uniquely to metabolically generated l-MeAmp but also to other actions of deprenyl at the dopamine terminal.