Ticlopidine inhibition of phenytoin metabolism mediated by potent inhibition of CYP2C19
Ticlopidine inhibition of phenytoin metabolism mediated by potent inhibition of CYP2C19
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DOI：
10.1016/s0009-9236(97)90054-0
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发表时间：
1997-11-01
影响因子：
6.7
通讯作者：
Ko, JW
中科院分区：
文献类型：
--
作者：
Donahue, SR;Flockhart, DA;Ko, JW
一名服用稳定剂量苯妥英2年的患者因不稳定型心绞痛置入冠状动脉支架，并在其治疗方案中加入噻氯匹定。25天后，他因急性症状性苯妥英中毒住院，血清浓度为46.5 μ g/ml。代谢基因型的测定显示患者具有CTP 2C 9、CTP 2C 19和CTP 2D 6的野生型基因型。使用人肝微粒体，我们表明噻氯匹定是细胞色素P450 2C 19的强效抑制剂，估计抑制常数（Ki）为3.7 +/- 0.2 μ mol/L。噻氯匹定对代谢苯妥英的另一种细胞色素P450亚型CYP 2C 9的影响相对较弱，计算的Ki为38.8 +/- 27 μ mol/L。这些数据表明，在该患者中，苯妥英毒性是由噻氯匹定抑制CYP 2C 19引起的，这些数据强调了CYP 2C 19在苯妥英代谢中的重要性。
A patient who had taken a stable dose of phenytoin for 2 years had a coronary stent placed for unstable angina and ticlopidine was added to his therapeutic regimen. Twenty-five days later, he was hospitalized with acute symptomatic phenytoin toxicity and a serum concentration of 46.5 mu g/ml. Determination of metabolic genotype revealed that the patient had a wild-type genotype for CTP2C9, CTP2C19, and CTP2D6. Using human liver microsomes, we showed that ticlopidine is a potent inhibitor of cytochrome P450 2C19, with an estimated inhibition constant (K-i) of 3.7 +/- 0.2 mu mol/L. The influence of ticlopidine on CYP2C9, the other cytochrome P450 isoform that metabolizes phenytoin, is relatively weak, with a calculated K-i of 38.8 +/- 27 mu mol/L. These data suggest that, in this patient, phenytoin toxicity was caused by inhibition of CYP2C19 by ticlopidine, and the data emphasize the importance of CYP2C19 in the metabolism of phenytoin.