Selective Inhibition of Cytochrome P450 2D6 by Sarpogrelate and Its Active Metabolite, M-1, in Human Liver Microsomes
Selective Inhibition of Cytochrome P450 2D6 by Sarpogrelate and Its Active Metabolite, M-1, in Human Liver Microsomes
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沙格雷酯及其活性代谢物 M-1 对人肝微粒体中细胞色素 P450 2D6 的选择性抑制
DOI：
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发表时间：
2014
影响因子：
3.9
通讯作者：
S. Bae
中科院分区：
文献类型：
--
作者：
Doo;S. Bae;Joeng Kee Lee;Y. Kim;Bom;S. Bae
本文研究了沙波吉及其活性代谢物M-1对9种人细胞色素(CYP)亚型活性的体外抑制作用。采用鸡尾酒试验，通过人肝微粒体中的特异性标记反应，检测了沙波吉利对9种CYP亚型和M-1的影响。Sarpogrelate以竞争性方式有效和选择性地抑制细胞色素P_2 D_6介导的右美沙芬O-去甲基化，其IC50(Ki)值为3.05μM(1.24μM)。M-1对细胞色素P450_2D6也有明显的抑制作用，其IC50(Ki)值为0.201μM(0.120μM)强于沙培林，与著名的典型的细胞色素P450酶抑制剂奎尼丁(Ki，0.129μM)的抑制作用相当。此外，沙波吉和M-1对细胞色素P450_2D6催化的丁香酚1‘-羟化和美托洛尔α-羟化均有强烈的抑制作用。然而，Sarpogrell和M-1对其他8种细胞色素P450酶：CYP1A2、CYP2A6、CYP2B6、CYP2C8、CYP2C9、CYP2C19、CYP2E1或CYP3A4/5没有明显的抑制作用。在NADPH存在下，Sarpogrelate和M-1与人肝微粒体预先孵育30分钟后，对9种CYP活性的抑制没有明显的IC50变化，表明Sarpogrelate和M-1不是时间依赖的失活剂。Sarpogrelate在临床相关浓度下强烈抑制人肝微粒体中CYP2D6的活性。这些观察表明，Sarpogrelate可能会影响以CYP2D6催化的代谢为主要清除途径的药物的代谢清除，从而引发药物与药物之间的药代动力学相互作用。
The present study was performed to evaluate the in vitro inhibitory potential of sarpogrelate and its active metabolite, M-1, on the activities of nine human cytochrome (CYP) isoforms. Using a cocktail assay, the effects of sarpogrelate on nine CYP isoforms and M-1 were measured by specific marker reactions in human liver microsomes. Sarpogrelate potently and selectively inhibited CYP2D6-mediated dextromethorphan O-demethylation with an IC50 (Ki) value of 3.05 μM (1.24 μM), in a competitive manner. M-1 also markedly inhibited CYP2D6 activity; its inhibitory effect with an IC50 (Ki) value of 0.201 μM (0.120 μM) was more potent than that of sarpogrelate, and was similarly potent as quinidine (Ki, 0.129 μM), a well-known typical CYP2D6 inhibitor. In addition, sarpogrelate and M-1 strongly inhibited both CYP2D6-catalyzed bufuralol 1′-hydroxylation and metoprolol α-hydroxylation activities. However, sarpogrelate and M-1 showed no apparent inhibition of the other following eight CYPs: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A4/5. Upon 30-minute preincubation of human liver microsomes with sarpogrelate or M-1 in the presence of NADPH, no obvious shift in IC50 was observed in terms of inhibition of the nine CYP activities, suggesting that sarpogrelate and M-1 are not time-dependent inactivators. Sarpogrelate strongly inhibited the activity of CYP2D6 at clinically relevant concentrations in human liver microsomes. These observations suggest that sarpogrelate could have an effect on the metabolic clearance of drugs possessing CYP2D6-catalyzed metabolism as a major clearance pathway, thereby eliciting pharmacokinetic drug–drug interactions.
影响因子：
3.9
作者：
Clarke, TA;Waskell, LA
通讯作者：
Waskell, LA
用选择性血清素再摄取抑制剂治疗的患者中氯氮平和去甲氯氮平的血清水平。
DOI：
10.1176/ajp.153.6.820
发表时间：
1996
期刊：
The American journal of psychiatry
影响因子：
--
作者：
Centorrino,F;Baldessarini,RJ;Frankenburg,FR;Kando,J;Volpicelli,SA;Flood,JG
通讯作者：
Flood,JG