Uehara Shotaro, Ishii Sakura, Uno Yasuhiro, Inoue Takashi, Sasaki Erika, Yamazaki Hiroshi
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.)
Drug Metab Dispos. 2017 Aug;45(8):896-899. doi: 10.1124/dmd.117.075630. Epub 2017 May 11.
A -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 () 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 -metoprolol -demethylation and -metoprolol -hydroxylation, respectively, those from humans, marmosets, minipigs, and dogs preferentially mediated -metoprolol -demethylation, in contrast to the slow rates of - and -metoprolol oxidation in mouse liver microsomes. - and -metoprolol -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 -metoprolol -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.
β受体阻滞剂美托洛尔是人类细胞色素P450（P450）2D6的体内探针之一。对非人灵长类动物P450酶的研究有助于提高将药代动力学数据从动物外推至人类的准确性。普通狨猴（Callithrix jacchus）是临床前研究的潜在灵长类动物模型，但狨猴P450酶在美托洛尔氧化中的具体作用仍不清楚。在本研究中，体外研究了多种P450酶对狨猴和人肝脏中美托洛尔氧化的区域选择性和立体选择性。尽管食蟹猴和大鼠的肝微粒体分别优先介导β-美托洛尔的N-去甲基化和α-美托洛尔的O-羟基化，但人、狨猴、小型猪和犬的肝微粒体优先介导β-美托洛尔的N-去甲基化，与之形成对比的是，小鼠肝微粒体中α-和β-美托洛尔的氧化速率较慢。狨猴肝脏中α-和β-美托洛尔的N-去甲基化活性受到奎尼丁和酮康唑的强烈抑制，并且与布非洛尔1'-羟基化和咪达唑仑1'-羟基化活性以及P450 2D和3A4含量显著相关，这与人类肝脏的情况不同，人类肝脏中与P450 3A介导的咪达唑仑1'-羟基化没有任何相关性。重组人P450 2D6酶和狨猴P450 2D6/3A4酶分别有效地催化β-美托洛尔的N-去甲基化，其活性分别与人及狨猴肝微粒体相当。这些结果表明，P450 2D酶在美托洛尔氧化的区域选择性和立体选择性方面的主要作用在人和狨猴肝脏中相似，但P450 3A酶的次要作用在狨猴中是独特的。
