Tags

Type your tag names separated by a space and hit enter

Regio- and Stereo-Selective Oxidation of a Cardiovascular Drug, Metoprolol, Mediated by Cytochrome P450 2D and 3A Enzymes in Marmoset Livers.
Drug Metab Dispos. 2017 08; 45(8):896-899.DM

Abstract

A β-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 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 the slow rates of R- and S-metoprolol oxidation 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, which is different from the case in human livers that did not have any correlations with P450 3A-mediated midazolam 1'-hydroxylation. 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 oxidation were similar between human and marmoset livers, but the minor roles of P450 3A enzymes were unique to marmosets.

Authors+Show Affiliations

Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan (S.U., S.I., H.Y.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Wakayama, Japan (Y.U.); Department of Applied Developmental Biology (T.I.) and Center of Applied Developmental Biology (E.S.), Central Institute for Experimental Animals, Kawasaki, Japan; and Keio Advanced Research Center, Keio University, Minato-ku, Tokyo, Japan (E.S.).Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan (S.U., S.I., H.Y.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Wakayama, Japan (Y.U.); Department of Applied Developmental Biology (T.I.) and Center of Applied Developmental Biology (E.S.), Central Institute for Experimental Animals, Kawasaki, Japan; and Keio Advanced Research Center, Keio University, Minato-ku, Tokyo, Japan (E.S.).Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan (S.U., S.I., H.Y.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Wakayama, Japan (Y.U.); Department of Applied Developmental Biology (T.I.) and Center of Applied Developmental Biology (E.S.), Central Institute for Experimental Animals, Kawasaki, Japan; and Keio Advanced Research Center, Keio University, Minato-ku, Tokyo, Japan (E.S.).Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan (S.U., S.I., H.Y.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Wakayama, Japan (Y.U.); Department of Applied Developmental Biology (T.I.) and Center of Applied Developmental Biology (E.S.), Central Institute for Experimental Animals, Kawasaki, Japan; and Keio Advanced Research Center, Keio University, Minato-ku, Tokyo, Japan (E.S.).Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan (S.U., S.I., H.Y.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Wakayama, Japan (Y.U.); Department of Applied Developmental Biology (T.I.) and Center of Applied Developmental Biology (E.S.), Central Institute for Experimental Animals, Kawasaki, Japan; and Keio Advanced Research Center, Keio University, Minato-ku, Tokyo, Japan (E.S.).Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan (S.U., S.I., H.Y.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Wakayama, Japan (Y.U.); Department of Applied Developmental Biology (T.I.) and Center of Applied Developmental Biology (E.S.), Central Institute for Experimental Animals, Kawasaki, Japan; and Keio Advanced Research Center, Keio University, Minato-ku, Tokyo, Japan (E.S.) hyamazak@ac.shoyaku.ac.jp.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28495902

Citation

Uehara, Shotaro, et al. "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, vol. 45, no. 8, 2017, pp. 896-899.
Uehara S, Ishii S, Uno Y, et al. Regio- and Stereo-Selective Oxidation of a Cardiovascular Drug, Metoprolol, Mediated by Cytochrome P450 2D and 3A Enzymes in Marmoset Livers. Drug Metab Dispos. 2017;45(8):896-899.
Uehara, S., Ishii, S., Uno, Y., Inoue, T., Sasaki, E., & Yamazaki, H. (2017). 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, 45(8), 896-899. https://doi.org/10.1124/dmd.117.075630
Uehara S, et al. Regio- and Stereo-Selective Oxidation of a Cardiovascular Drug, Metoprolol, Mediated By Cytochrome P450 2D and 3A Enzymes in Marmoset Livers. Drug Metab Dispos. 2017;45(8):896-899. PubMed PMID: 28495902.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Regio- and Stereo-Selective Oxidation of a Cardiovascular Drug, Metoprolol, Mediated by Cytochrome P450 2D and 3A Enzymes in Marmoset Livers. AU - Uehara,Shotaro, AU - Ishii,Sakura, AU - Uno,Yasuhiro, AU - Inoue,Takashi, AU - Sasaki,Erika, AU - Yamazaki,Hiroshi, Y1 - 2017/05/11/ PY - 2017/02/21/received PY - 2017/05/10/accepted PY - 2017/5/13/pubmed PY - 2018/2/6/medline PY - 2017/5/13/entrez SP - 896 EP - 899 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 45 IS - 8 N2 - A β-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 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 the slow rates of R- and S-metoprolol oxidation 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, which is different from the case in human livers that did not have any correlations with P450 3A-mediated midazolam 1'-hydroxylation. 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 oxidation were similar between human and marmoset livers, but the minor roles of P450 3A enzymes were unique to marmosets. SN - 1521-009X UR - https://www.unboundmedicine.com/medline/citation/28495902/Regio__and_Stereo_Selective_Oxidation_of_a_Cardiovascular_Drug_Metoprolol_Mediated_by_Cytochrome_P450_2D_and_3A_Enzymes_in_Marmoset_Livers_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=28495902 DB - PRIME DP - Unbound Medicine ER -