Acenocoumarol与细胞色素P450 2C9基因型的药代动力学研究。

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Thijssen HH, Ritzen B

Acenocoumarol与细胞色素P450 2C9基因型的药代动力学研究。

临床药物学杂志2003七月;74(1):61-8。doi: 10.1016 / s0009 - 9236(03) 00088 - 2。

PubMed ID

12844136 (PubMed视图

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摘要

背景与目的:细胞色素P450 (CYP) 2C9是参与药物生物转化的主要CYP酶之一，其中包括口服抗凝血药阿辛库玛洛。该酶具有几种多态性，其中CYP2C9*2和CYP2C9*3变体最常出现在白人患者中。已知CYP2C9*3变异的患者需要较低的外消旋香辛醇维持剂量。我们研究了CYP2C9*2和CYP2C9*3基因多态性对R-和s -乙酰香豆素药代动力学的影响。方法与结果:在第一项研究中，26名基因型为*1/*1 (n = 9)、*1/*2 (n = 7)、*1/*3 (n = 6)、*2/*3 (n = 3)和*2/*2 (n = 1)的健康志愿者单次口服8 mg外消旋香豆素。分别于4,7,24小时测定血浆R-和S-acenocoumarol浓度。具有变异等位基因的受试者7小时的平均血浆S-acenocoumarol浓度较高;*1/*3和*2/*3基因型间差异有统计学意义(P =.01)。在第二项研究中，对6名受试者(*1/*1 [n = 3]和*1/*3 [n = 3])进行了acenocoumarol的口服药代动力学研究。CYP2C9*1/*3基因型S-acenocoumarol的平均口服清除率低45% (10.9 +/- 3.0 L/h vs 19.8 +/- 3.1 L/h, P =.02)。 Plasma half-life was prolonged from 1.0 +/- 0.2 hours to 2.0 +/- 0.7 hours (P =.09). R-acenocoumarol pharmacokinetics did not differ between the genotypes. There was no difference in mean international normalized ratio at 24 hours, which was 1.2 in both groups. In vitro enzyme kinetics showed reduced (85%) intrinsic activity of the *3 enzyme to catalyze the hydroxylations of S-acenocoumarol. The lower activity resulted from higher Michaelis-Menten constant (2-fold) and lower maximum rate of metabolism by an enzyme-mediated reaction (by 70%). The activity of the *2 enzyme was 50% of the wild-type one. CONCLUSION: The results show S-acenocoumarol pharmacokinetics to be dependent on CYP2C9 polymorphism. In particular, the presence of the CYP2C9*3 allele impairs oral clearance of the coumarin.

引用本文的药物库数据

药物酶

药物	酶	种类	生物	药理作用	行动
苊香豆醇	细胞色素P450 2C9	蛋白质	人类	未知的	底物	细节