The influence of metabolism on the MAO-B inhibitory potency of selegiline.
(-)-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.
Haberle
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Department of Pharmacodynamics Semmelweis University, H-1445 Budapest, Hungary. szokeva@net.sote.hu
Szökõ
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Magyar
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D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008995:Monoamine Oxidase / Q000096:biosynthesis / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D010634:Phenobarbital / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012642:Selegiline / Q000493:pharmacokinetics* / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D008996:Monoamine Oxidase Inhibitors; D012642:Selegiline; D011335:Proadifen; D008995:Monoamine Oxidase; D010634:Phenobarbital