Metabolism of methoxyphenamine in vitro by a CYP2D6 microsomal preparation.
Metabolism of methoxyphenamine (MP) was conducted in vitro using commercially available microsomes prepared from human AHH-1 TK+/-cells in which CYP2D6 had been expressed. This study has confirmed the involvement of CYP2D6 in the metabolism of MP to O-desmethylmethoxyphenamine (ODMP) and 5-hydroxymethoxyphenamine (5HMP), but not to N-desmethylmethoxyphenamine. It has also revealed that CYP2D6 catalyzes the formation of another, hitherto unknown, ring-hydroxylated metabolite of MP, isomeric with 5HMP. The analytical procedure used to identify and quantify MP metabolites involved an acetylation procedure that had distinct advantages. MP and its basic and amphoteric metabolites were all converted to neutral products that were efficiently extracted into organic solvent. The acetylated products also had good chromatographic properties and provided mass spectra that were readily interpretable. MP metabolism studies were also conducted with CYP2D6 microsomes in the presence of quinidine and quinine. The former was the more potent inhibitor of CYP2D6-catalyzed oxidations of MP. Its inclusion resulted in complete inhibition of metabolism of MP to ODMP, 5HMP, and its novel isomer. This study shows that the in vitro use of human cytochrome P450 isozyme preparations in drug metabolism studies can aid in the identification of possible in vivo metabolites of these drugs in humans and can provide information on putative drug-drug interactions.
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Canada.
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D000107:Acetylation; D000318:Adrenergic beta-Agonists / Q000378:metabolism*; D001711:Biotransformation; D002478:Cells, Cultured; D002849:Chromatography, Gas; D019389:Cytochrome P-450 CYP2D6; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D008694:Methamphetamine / Q000031:analogs & derivatives* / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011802:Quinidine / Q000494:pharmacology; D011803:Quinine / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D065607:Cytochrome P-450 Enzyme Inhibitors; D008694:Methamphetamine; D003577:Cytochrome P-450 Enzyme System; D011803:Quinine; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D011802:Quinidine; C005157:methoxyphenamine