PT - JOURNAL ARTICLE AU - Shotaro Uehahara AU - Sakura Ishii AU - Yasuhiro Uno AU - Takashi Inoue AU - Erika Sasaki AU - Hiroshi Yamazaki TI - Regio- and stereo-selective oxidation of a cardiovascular drug metoprolol mediated by cytochrome P450 2D and 3A enzymes in marmoset livers AID - 10.1124/dmd.117.075630 DP - 2017 Jan 01 TA - Drug Metabolism and Disposition PG - dmd.117.075630 4099 - http://dmd.aspetjournals.org/content/early/2017/05/11/dmd.117.075630.short 4100 - http://dmd.aspetjournals.org/content/early/2017/05/11/dmd.117.075630.full AB - A β-blocker metoprolol is one of the in vivo probes for human cytochrome P450 (P450) 2D6. Investigation of non-human primate P450 enzymes helps improve accuracy of the extrapolation of pharmacokinetic data from animals into humans. Common marmosets (Callithrix jacchus) are a potential primate model for preclinical research, but detailed roles of marmoset P450 enzymes in metoprolol oxidations remained unknown. In this study, regio- and stereo-selectivity of metoprolol oxidations by a variety of P450 enzymes in marmoset and human livers were investigated in vitro. Although liver microsomes from cynomolgus monkeys and rats preferentially mediated S-metoprolol O-demethylation and R-metoprolol α-hydroxylation, respectively, those from humans, marmosets, minipigs, and dogs preferentially mediated R-metoprolol O-demethylation, in contrast to slow rates of R- and S-metoprolol oxidations in mouse liver microsomes. R- and S-metoprolol O-demethylation activities in marmoset livers were strongly inhibited by quinidine and ketoconazole, and were significantly correlated with bufuralol 1'-hydroxylation and midazolam 1'-hydroxylation activities and also with P450 2D and 3A4 contents, different from the cases in human livers which did not have any correlations with P450 3A-mediated midazolam 1'-hydroxylations. Recombinant human P450 2D6 enzyme and marmoset P450 2D6/3A4 enzymes effectively catalyzed R-metoprolol O-demethylation, comparable to the activities of human and marmoset liver microsomes, respectively. These results indicated that the major roles of P450 2D enzymes for the regio- and stereo-selectivity of metoprolol oxidations were similar between human and marmoset livers, but the minor roles of P450 3A enzymes were unique to marmosets.