In vivo individual variations in pharmacokinetics of efavirenz in cynomolgus monkeys genotyped for cytochrome P450 2C9.
In vivo individual variations in pharmacokinetics of efavirenz in cynomolgus monkeys genotyped for cytochrome P450 2C9.
复制标题
细胞色素 P450 2C9 基因分型的食蟹猴中依非韦伦药代动力学的体内个体差异。
DOI：
10.1002/bdd.2021
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
H.
中科院分区：
文献类型：
--
作者：
Iwasaki;K.;Kitsugi;Y.;Ikeda;K.;Yoshikawa;T.;Hosaka;S.;Uehara;S.;Uno;Y.;Utoh;M.;and Yamazaki;H.
由于食蟹猴与人类在进化上的接近性，食蟹猴经常用于新药开发的临床前研究。抗逆转录病毒药物依法韦仑是人细胞色素P450（P450）2B 6的典型探针底物，但主要由食蟹猴P450 2C 9代谢。在本研究中，通过高效液相色谱-串联质谱法评估了6只基因型为P450 2C9c.334 A > C（I112 L）的食蟹猴（3只野生型、1只杂合子和2只纯合子）的依法韦仑血浆浓度。以1.0 mg/kg剂量静脉给药后，在这些食蟹猴中观察到依法韦仑的双相血浆消除曲线。野生型组中主要代谢产物8-羟基依法韦仑的平均血浆浓度（治疗后1 h，通过β-葡萄糖醛酸酶水解）显著高于（4.0倍）杂合子和纯合子组的合并平均值。以2.0 mg/kg剂量经口给药后，纯合组中依法韦仑的血浆浓度-时间曲线下面积值显着高于野生型和杂合组（2.0倍）。这些结果表明P450 2C 9 c. 334 A > C（I112 L）多态性与依法韦仑体内代谢清除相关，食蟹猴P450 2C 9多态性可能是依法韦仑体内代谢的个体间差异。版权所有© 2016约翰威利父子有限公司.
Cynomolgus monkeys are used frequently in preclinical studies for new drug development due to their evolutionary closeness to humans. An antiretroviral drug, efavirenz, is a typical probe substrate for human cytochrome P450 (P450) 2B6, but is mainly metabolized by cynomolgus monkey P450 2C9. In this study, plasma concentrations of efavirenz were assessed in six cynomolgus monkeys genotyped forP450 2C9c.334 A > C (I112L) (three wild‐type, one heterozygote and two homozygotes) by high performance liquid chromatography with tandem mass spectrometry. After intravenous administration at a dose of 1.0 mg/kg, biphasic plasma elimination curves of efavirenz were seen in these cynomolgus monkeys. The mean plasma concentration of the primary metabolite 8‐hydroxyefavirenz (1 h after treatment, with hydrolysis by β‐glucuronidase) in the wild‐type group was significantly higher (4.0‐fold) than the combined heterozygous and homozygous group mean. The area under the plasma concentration–time curve value of efavirenz in the homozygous group after oral administration at a dose of 2.0 mg/kg was significantly higher (2.0‐fold) than the combined wild‐type and heterozygous group. These results collectively indicated thatP450 2C9c.334 A > C (I112L) variation was associated with efavirenz metabolic clearancein vivo.CynomolgusP450 2C9polymorphism might account for interindividual variations of efavirenz metabolism in cynomolgus monkeys. Copyright © 2016 John Wiley & Sons, Ltd.