(-)-Deprenyl (selegiline), a propargylamine derivative of methylamphetamine, is a potent, irreversible inhibitor of monoamine-oxidase type B (MAO-B). The MAO-B inhibitory effects of various doses (0.1-0.25-0.5 mg/kg) of (-)-deprenyl in rat brain and liver were compared, using either oral or subcutaneous drug administration. The intensity of the first pass metabolism of (-)-deprenyl was also estimated. The effect of pre-treatment with phenobarbitone (80 mg/kg i.p., daily for three days) or proadifen (SKF-525A, 50 mg/kg i.p., single dose) on the MAO-B inhibitory potency of (-)-deprenyl was also studied. The oral and subcutaneous administration of selegiline induced a significantly different degree of MAO-B enzyme inhibition in the rat brain, but not in the liver. The inhibitory potency of (-)-deprenyl on MAO-B activity was markedly influenced by pre-treatment of rats with an inducer (phenobarbitone), or an inhibitor (SKF-525A) of cytochrome P-450 mono-oxygenases in the liver. Our results suggest, that (-)-deprenyl is metabolised mainly in the liver by microsomal cytochrome P-450 dependent mono-oxygenases, and it has an intensive first-pass metabolism. The parent compound is responsible for the inhibition of MAO-B enzyme activity.

Analysis of Deprenyl Metabolites in the Rat Brain Using HPLC-ES-MS -[28 refs.]. -(KALASZ, H.; BARTOK, T.; KOMOROCZY, R.; SZOEKO, E.; HABERLE, D.; KISS, J. P.; HENNINGS, E. C. P.; MAGYAR, K.; FUERST, S.; Curr. Med. Chem. 6 (1999) 4, 271-278; Dep. Pharmacol. Pharmacotherap., Semmelweis Univ. Med., H-1445 Budapest, Hung.; EN)

Liquid chromatography (LC) combined with electrochemical detection (EC) is suitable for measuring oxidizable biogenic amine levels in small samples of brain tissue. The norepinephrine (NE) content in mouse hippocampus after treatment with various monoamine oxidase-B enzyme (MAO-B) inhibitors ([-]-deprenyl, [+]-rasagiline, and the noradrenergic neurotoxin N-[2-chloroethyl]-N-ethyl-2-bromobenzylamine [DSP-4]) is determined using an LC-EC method. Treatment with a single intraperitoneal dose of (-)-deprenyl (selegiline) before DSP-4 administration markedly reduces the NE depleting effect of the toxin, and (+)-rasagiline does not significantly modify the NE level decreased by the neurotoxin. The MAO-B inhibitory potency of (-)-deprenyl and (+)-rasagiline is also evaluated. Significantly reduced MAO-B enzyme activity in mouse brain and liver is measured 6 h after treatment with their single dose. (+)-Rasagiline is found to be a more potent MAO-B inhibitor than (-)-deprenyl.

Treatment with a single oral dose of (-)-deprenyl (selegiline) before DSP-4 administration could dose-dependently decrease the noradrenaline (NA) depleting effect of the toxin in mouse hippocampus. The maximum protective effect was achieved at as low oral dose as 0.25 mg/kg. Pre-treatment with the same doses of the main metabolites of (-)-deprenyl; (-)-amphetamine and (-)-methylamphetamine provided a weaker attenuation of DSP-4 induced NA depletion, than the parent compound. The selective noradrenergic toxin DSP-4, which depletes NA in nerve terminals originating from the locus coeruleus, is presumably metabolised by CYP-450 enzymes. Continuous administration of low, by themselves non-toxic doses of DSP-4 resulted in the cumulation of its NA depleting effect.

SummaryDeprenyl metabolites were analyzed in various organs of rats after chronic oral treatment. The investigation was carried out by gas chromatography combined with MSD after derivatization of the metabolites. When (-)-deprenyl (selegiline) was administered to rats higher ratios of methamphetamine to amphetamine were found in the kidney, and the heart at 1 and 5 h after treatment, than after (+)-deprenyl administration. Both deprenyl and its demethylated metabolite were also detected; however, their level was generally lower than that of either methamphetamine or amphetamine. Coadministration of verapamil with selegiline did not essentially alter the major metabolic pathway of deprenyl metabolism.