PT - JOURNAL ARTICLE AU - William P. Melega AU - Arthur K. Cho AU - Debra Schmitz AU - Ronald Kuczenski AU - David S. Segal TI - <em>l-</em>Methamphetamine Pharmacokinetics and Pharmacodynamics for Assessment of In Vivo Deprenyl-Derived<em>l-</em>Methamphetamine DP - 1999 Feb 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 752--758 VI - 288 IP - 2 4099 - http://jpet.aspetjournals.org/content/288/2/752.short 4100 - http://jpet.aspetjournals.org/content/288/2/752.full SO - J Pharmacol Exp Ther1999 Feb 01; 288 AB - 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 andl-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 forl-MeAmp (3 nmol/g) at 30 min. In a parallel study,l-MeAmp metabolism was evaluated. Afterl-MeAmp (20 mg/kg s.c.), metabolite levels remained low relative to those of the parent compound: l-amphetamine, ∼5 to 12%; andpara-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/kgl-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. The American Society for Pharmacology and Experimental Therapeutics