Kinetics of in vitro metabolism of methoxyphenamine in rats.
1. Methoxyphenamine (MP) was metabolized in vitro by rat liver preparations to O-desmethylmethoxyphenamine (O-desmethyl-MP), N-desmethylmethoxyphenamine (N-desmethyl-MP) and 5-hydroxymethoxyphenamine (5-hydroxy-MP). These metabolic pathways were inhibited by SKF 525-A and carbon monoxide, which indicates that these reactions were mediated at least partly by an NADPH-dependent cytochrome P-450 system. 2. Strain differences in the metabolism of this drug in vitro were observed in female Lewis and Dark Agouti (DA) rats, which are proposed models for human debrisoquine phenotypes. Methoxyphenamine O-demethylase and 5-hydroxylase activity in DA rats were lower than those in Lewis rats. 3. The metabolic transformation of methoxyphenamine in vitro to O-desmethyl-MP was inhibited competitively by debrisoquine and sparteine. This indicates that the cytochrome P-450 isoenzyme mediating the metabolism of MP to O-desmethyl-MP is similar to that mediating metabolism of debrisoquine and sparteine. However, no inhibition was observed with methenytoin.
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College of Pharmacy, University of Saskatchewan, Saskatoon, Canada.
D000818:Animals; D002849:Chromatography, Gas; D003647:Debrisoquin / Q000494:pharmacology; D005260:Female; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008694:Methamphetamine / Q000031:analogs & derivatives* / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010090:Oxidoreductases, O-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010640:Phenothiazines / Q000494:pharmacology; D051381:Rats; D013034:Sparteine / Q000494:pharmacology; D015262:Xenobiotics
D006571:Heterocyclic Compounds; D010640:Phenothiazines; D015262:Xenobiotics; D013034:Sparteine; D008694:Methamphetamine; D010088:Oxidoreductases; D010090:Oxidoreductases, O-Demethylating; D010089:Oxidoreductases, N-Demethylating; C005157:methoxyphenamine; D003647:Debrisoquin