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首页> 美国卫生研究院文献>Frontiers in Pharmacology >Cytochrome P450 Enzymes Involved in Metoprolol Metabolism and Use of Metoprolol as a CYP2D6 Phenotyping Probe Drug
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Cytochrome P450 Enzymes Involved in Metoprolol Metabolism and Use of Metoprolol as a CYP2D6 Phenotyping Probe Drug

机译：细胞色素P450酶参与美托洛尔代谢和美托洛尔作为CYP2D6表型探针药物的用途

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Metoprolol is used for phenotyping of cytochrome P450 (CYP) 2D6, a CYP isoform considered not to be inducible by inducers of the CYP2C, CYP2B, and CYP3A families such as rifampicin. While assessing CYP2D6 activity under basal conditions and after pre-treatment with rifampicin in vivo, we surprisingly observed a drop in the metoprolol/α-OH-metoprolol clearance ratio, suggesting CYP2D6 induction. To study this problem, we performed in vitro investigations using HepaRG cells and primary human hepatocytes (before and after treatment with 20 μM rifampicin), human liver microsomes, and CYP3A4-overexpressing supersomes. While mRNA expression levels of CYP3A4 showed a 15- to 30-fold increase in both cell models, mRNA of CYP2D6 was not affected by rifampicin. 1′-OH-midazolam formation (reflecting CYP3A4 activity) increased by a factor of 5–8 in both cell models, while the formation of α-OH-metoprolol increased by a factor of 6 in HepaRG cells and of 1.4 in primary human hepatocytes. Inhibition studies using human liver microsomes showed that CYP3A4, 2B6, and 2C9 together contributed 19.0 ± 2.6% (mean ± 95%CI) to O-demethylation, 4.0 ± 0.7% to α-hydroxylation, and 7.6 ± 1.7% to N-dealkylation of metoprolol. In supersomes overexpressing CYP3A4, metoprolol was α-hydroxylated in a reaction inhibited by the CYP3A4-specific inhibitor ketoconazole, but not by the CYP2D6-specific inhibitor quinidine. We conclude that metoprolol is not exclusively metabolized by CYP2D6. CYP3A4, 2B6, and 2C9, which are inducible by rifampicin, contribute to α-hydroxylation, O-demethylation, and N-dealkylation of metoprolol. This contribution is larger after CYP induction by rifampicin but is too small to compromise the usability of metoprolol α-hydroxylation for CYP2D6 phenotyping.
机译：美托洛尔用于细胞色素P450（CYP）2D6的表型分析，CYP 2D6被认为不能被CYP2C，CYP2B和CYP3A家族的诱导剂（如利福平）诱导。在基础条件下和体内利福平预处理后评估CYP2D6活性时，我们意外地观察到美托洛尔/α-OH-美托洛尔清除率下降，提示CYP2D6诱导。为研究此问题，我们使用HepaRG细胞和原代人肝细胞（用20μM利福平治疗之前和之后），人肝微粒体和CYP3A4过表达超体进行了体外研究。尽管在两种细胞模型中CYP3A4的mRNA表达水平都增加了15至30倍，但CYP2D6的mRNA不受利福平的影响。在两种细胞模型中，1'-OH-咪达唑仑的形成（反映CYP3A4活性）增加5-8倍，而在HepaRG细胞中α-OH-美托洛尔的形成增加6倍，在原代人肝细胞中增加1.4倍。使用人肝微粒体的抑制研究表明，CYP3A4、2B6和2C9一起对O-去甲基化贡献了19.0±2.6％（平均值±95％CI），对α-羟基化贡献了4.0±0.7％，对N-去烷基化贡献了7.6±1.7％美托洛尔。在过表达CYP3A4的超体中，美托洛尔在被CYP3A4特异性抑制剂酮康唑抑制，但未被CYP2D6特异性抑制剂奎尼丁抑制的反应中被α-羟基化。我们得出的结论是美托洛尔不仅仅被CYP2D6代谢。利福平可诱导的CYP3A4、2B6和2C9有助于美托洛尔的α-羟基化，O-去甲基化和N-去烷基化。在利福平进行CYP诱导后，此贡献较大，但过小而无法影响美托洛尔α-羟基化对CYP2D6表型的可用性。

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