Effect of antipsychotic drugs on human liver cytochrome P-450 (CYP) isoforms in vitro: preferential inhibition of CYP2D6.
Effect of antipsychotic drugs on human liver cytochrome P-450 (CYP) isoforms in vitro: preferential inhibition of CYP2D6.
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发表时间：
1999-09
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通讯作者：
Jae-Gook Shin;N. Soukhova;D. Flockhart
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作者：
Jae-Gook Shin;N. Soukhova;D. Flockhart
使用体外人肝微粒体制剂比较抗精神病药物抑制5种细胞色素P-450（CYP）亚型催化活性的能力，以评价这些药物抑制药物代谢的相对潜力。通过对数据的非线性回归分析，确定了酶抑制的表观动力学参数。所有测试的抗精神病药物都以浓度依赖性方式竞争性抑制CYP 2D 6的选择性标志物--美沙芬O-去甲基化。硫利达嗪和奋乃静是最有效的，IC（50）值（2.7和1.5 μ M）与奎尼丁（0.52 μ M）相当。CYP 2D 6催化右啡烷形成的估计K（i）值按以下顺序排列：奋乃静（0.8 μ M）、硫利达嗪（1.4 μ M）、氯丙嗪（6.4 μ M）、氟哌啶醇（7.2 μ M）、氟奋乃静（9.4 μ M）、利培酮（21.9 μ M）、氯氮平（39.0 μ M）和顺式硫代噻吨（65.0 μ M）。除了氟奋乃静（K（i）= 40.2 μ M）和奋乃静（K（i）= 65.1）对CYP 1A 2催化的非那西丁O-脱乙基反应有中度抑制作用外，未观察到对其他β亚型的显著抑制作用。在几乎所有测试的抗精神病药物中，抑制CYP 2C 9、2C 19和3A的估计K（i）值均>300 μ M。这些结果表明，与其他CYP 2D 6亚型相比，抗精神病药物对CYP 2D 6表现出惊人的选择性。这可能反映了这些药物的治疗靶点、转运蛋白和分布和消除它们的代谢酶之间的结构的显著共性。临床上，这些药物与主要通过CYP 2D 6代谢的药物联合给药可能导致显著的药物相互作用。
The ability of antipsychotic drugs to inhibit the catalytic activity of five cytochrome P-450 (CYP) isoforms was compared using in vitro human liver microsomal preparations to evaluate the relative potential of these drugs to inhibit drug metabolism. The apparent kinetic parameters for enzyme inhibition were determined by nonlinear regression analysis of the data. All antipsychotic drugs tested competitively inhibited dextromethorphan O-demethylation, a selective marker for CYP2D6, in a concentration-dependent manner. Thioridazine and perphenazine were the most potent, with IC(50) values (2.7 and 1.5 microM) that were comparable to that of quinidine (0.52 microM). The estimated K(i) values for CYP2D6-catalyzing dextrorphan formation were ranked in the following order: perphenazine (0.8 microM), thioridazine (1.4 microM), chlorpromazine (6.4 microM), haloperidol (7.2 microM), fluphenazine (9.4 microM), risperidone (21.9 microM), clozapine (39.0 microM), and cis-thiothixene (65.0 microM). No remarkable inhibition of other CYP isoforms was observed except for moderate inhibition of CYP1A2-catalyzed phenacetin O-deethylation by fluphenazine (K(i) = 40.2 microM) and perphenazine (K(i) = 65.1). The estimated K(i) values for the inhibition of CYP2C9, 2C19, and 3A were >300 microM in almost all antipsychotics tested. These results suggest that antipsychotic drugs exhibit a striking selectivity for CYP2D6 compared with other CYP isoforms. This may reflect a remarkable commonality of structure between the therapeutic targets for these drugs, the transporters, and metabolic enzymes that distribute and eliminate them. Clinically, coadministration of these medicines with drugs that are primarily metabolized by CYP2D6 may result in significant drug interactions.