Pharmacokinetic studies of (-)-deprenyl and some of its metabolites in mouse.
(-)-Deprenyl is a selective irreversible inhibitor of MAO-B. The parent compound is responsible for the enzyme inhibitory effect, but its metabolites are also playing a role in the complex pharmacological activity of the substance. In the present studies male NMRI mice were treated orally, subcutaneously, intraperitoneally and intravenously with 5 mg/kg of (-)-deprenyl. The time related changes of the plasma concentrations of the parent compound and its main metabolites (methamphetamine, desmethyl-deprenyl and amphetamine) were determined by GC/ MSD technique. The main pharmacokinetic parameters (C(max), t(max), t1/2beta, AUC(0-6), AUC(0-infinity)) have been calculated. (-)-Deprenyl is well absorbed after oral and parental treatment. The peak concentrations (C(max)) were reached at 15 min after treatment and the absorption was followed by a fast elimination (t1/2beta < or = 2h). (-)-Deprenyl has an intensive "first pass" metabolism after oral treatment; only 25% of the parent compound reaches the systemic circulation. Increased bioavailability was detected after subcutaneous (87.1%) and intraperitoneal (78.7%) administration. The main metabolic pathway of (-)-deprenyl is the N-depropargylation, leading to the formation of methamphetamine. N-demethylation of (-)-deprenyl leads to formation of desmethyl-deprenyl. Amphetamine is produced from both former metabolites. After oral treatment the plasma concentrations of methamphetamine are higher during the first 6 h than that of (-)-deprenyl, while the opposite was found after parental treatment. The results indicate, that (-)-deprenyl, a potent MAO-B inhibitor, might induce a different spectrum of activity (e.g. antidepressant), when it is administered parenterally (transdermally). The new spectrum can be due to the special pharmacokinetic behaviour of the inhibitor.
Magyar
K
K
Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary. kalman.magyar@net.sote.hu
Szatmáry
I
I
Szebeni
G
G
Lengyel
J
J
D000284:Administration, Oral; D000661:Amphetamine / Q000493:pharmacokinetics; D000662:Amphetamines / Q000493:pharmacokinetics; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D001711:Biotransformation / Q000502:physiology; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D008694:Methamphetamine / Q000493:pharmacokinetics; D051379:Mice; D008815:Mice, Inbred Strains; D008996:Monoamine Oxidase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012642:Selegiline / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000662:Amphetamines; D000978:Antiparkinson Agents; D008996:Monoamine Oxidase Inhibitors; D012642:Selegiline; D008694:Methamphetamine; C017861:desmethylselegiline; D000661:Amphetamine