Regio- and Stereo-Selective Oxidation of a Cardiovascular Drug, Metoprolol, Mediated by Cytochrome P450 2D and 3A Enzymes in Marmoset Livers

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Shotaro UeharaH Yamazaki

Abstract

Aβ-blocker, metoprolol, is one of the in vivo probes for human cytochrome P450 (P450) 2D6. Investigation of nonhuman primate P450 enzymes helps to improve the accuracy of the extrapolation of pharmacokinetic data from animals into humans. Common marmosets (Callithrix jacchus) are a potential primate model for preclinical research, but the detailed roles of marmoset P450 enzymes in metoprolol oxidation remain 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 mediatedS-metoprololO-demethylation andR-metoprololα-hydroxylation, respectively, those from humans, marmosets, minipigs, and dogs preferentially mediatedR-metoprololO-demethylation, in contrast to the slow rates ofR- andS-metoprolol oxidation in mouse liver microsomes.R- andS-metoprololO-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, which is different from the case in human livers that did n...Continue Reading

References

Jan 1, 1975·Acta Pharmacologica Et Toxicologica·K O BorgB Wallin
Dec 16, 2010·Regulatory Toxicology and Pharmacology : RTP·Antonia OrsiGermano Oberto
May 15, 2013·Clinical Pharmacology and Therapeutics·C M BlakeP Nagele
Mar 25, 2015·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Shotaro UeharaHiroshi Yamazaki
Aug 1, 2015·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Shotaro UeharaHiroshi Yamazaki
Jul 21, 2016·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Shotaro UeharaHiroshi Yamazaki
Feb 16, 2017·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Shotaro UeharaHiroshi Yamazaki

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Citations

Jan 1, 2019·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Shotaro UeharaHiroshi Suemizu

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