Effects of clopidogrel and itraconazole on the disposition of efavirenz and its hydroxyl metabolites: exploration of a novel CYP2B6 phenotyping index
Effects of clopidogrel and itraconazole on the disposition of efavirenz and its hydroxyl metabolites: exploration of a novel CYP2B6 phenotyping index
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DOI：
10.1111/j.1365-2125.2012.04314.x
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发表时间：
2013-01-01
影响因子：
3.4
通讯作者：
Shin, Jae-Gook
中科院分区：
文献类型：
--
作者：
Jiang, Fen;Desta, Zeruesenay;Shin, Jae-Gook
已知的细胞色素P450(CYP)2B6是主要负责许多临床重要药物代谢的酶，包括法韦伦兹，它转化为8-羟基法韦伦兹，然后转化为8-羟基法韦伦兹。CYP2B6*6基因多态影响Eefavirenz的药代动力学，但目前还没有一种有效的表型方法来预测受试者中的CYP2B6活性。8，14-二羟基黄连在人体内的分布尚不清楚。这项研究补充说，这项研究是首次对8，14-二羟基法韦仑在人体内的药代动力学进行定量检测。8，14-二羟基法韦仑：依法韦仑的AUC(0,120小时)与依法韦仑的口服清除量相关，并且对CYP2B6活性的改变敏感和特异。8，14-二羟基黄酮维酮：依沙韦林AUC(0,120h)的比值可能是体内CYP2B6活性的一个有用的表型指标。目的评价氯吡格雷和伊曲康唑对CYP2B6*6基因相关羟基代谢产物的影响，探讨小剂量口服依曲康唑对体内CYP2B6活性的潜在表型指标。方法对17例健康朝鲜族健康受试者进行了三阶段随机交叉研究，其中6例为CYP2B6*1/*1，6例为*1/*6，5例为*6/*6。受试者接受氯吡格雷(75 mg day-1，连用4天)、伊曲康唑(200 mg day-1，连用6天)或安慰剂的预治疗，然后给予单剂量的efavirenz(200 Mg)。采用LC/MS/MS法测定血浆(0120h)和尿液(024h)中依法韦仑及其3种羟基代谢物(7-和8-羟基法韦仑和8，14-二羟基法韦仑)的血药浓度和尿药浓度。氯吡格雷可显著降低8，14-二羟基法韦林的AUC(0，48h)、Cmax和Ae(0，24 h)，其95%CI分别为0.55、0.73、0.30、0.45和0.25、0.47。8，14-二羟基法韦仑：依曲康唑AUC(0,120h)比值与依曲康唑的体重调整CL/F显著相关(R2接近0.4，P<；0.05)，与CYP2B6*6不同，氯吡格雷干预对其有影响(P<；0.05)，但伊曲康唑对其影响不大。结论8，14-二羟基-EFV在人体内的分布对CYP2B6活性变化敏感。8，14-二羟基叶法韦林与依沙韦林AUC(0,120h)之比可作为体内细胞色素P450受体6活性的候选表型指标。
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Cytochrome P450 (CYP) 2B6 is the enzyme primarily responsible for the metabolism of many clinically important drugs, including efavirenz, which it converts to 8-hydroxyefavirenz and then to 8,14-hydroxyefavirenz. The CYP2B6*6 polymorphism influences efavirenz pharmacokinetics, but a validated phenotyping method for predicting CYP2B6 activity in human subjects is not yet available. The disposition of 8,14-dihydroxyefavirenz in humans in vivo is unknown. WHAT THIS STUDY ADDS This study is the first quantitative examination of 8,14-dihydroxyefavirenz pharmacokinetics in human subjects. The 8,14-dihydroxyefavirenz : efavirenz AUC(0,120 h) ratio correlates with efavirenz oral clearance and is sensitive and specific to CYP2B6 activity alterations. The 8,14-dihydroxyefavirenz : efavirenz AUC(0,120 h) ratio may be a useful phenotyping index for CYP2B6 activity in vivo. AIMS To evaluate the effects of clopidogrel and itraconazole on the disposition of efavirenz and its hydroxyl metabolites in relation to the CYP2B6*6 genotype and explore potential phenotyping indices for CYP2B6 activity in vivo using a low dose of oral efavirenz. METHODS We conducted a randomized three phase crossover study in 17 healthy Korean subjects pre-genotyped for the CYP2B6*6 allele (CYP2B6*1/*1, n= 6; *1/*6, n= 6; *6/*6, n= 5). Subjects were pretreated with clopidogrel (75 mg day-1 for 4 days), itraconazole (200 mg day-1 for 6 days), or placebo and then given a single dose of efavirenz (200 mg). The plasma (0120 h) and urine (024 h) concentrations of efavirenz and its metabolites (7- and 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz) were determined by LC/MS/MS. RESULTS This study is the first to delineate quantitatively the full (phase I and II) metabolic profile of efavirenz and its three hydroxyl metabolites in humans. Clopidogrel pretreatment markedly decreased AUC(0,48 h), Cmax and Ae(0,24 h) for 8,14-dihydroxyefavirenz, compared with placebo; 95% CI of the ratios were 0.55, 0.73, 0.30, 0.45 and 0.25, 0.47, respectively. The 8,14-dihydroxyefavirenz : efavirenz AUC(0,120 h) ratio was significantly correlated with the weight-adjusted CL/F of efavirenz (r2 approximate to 0.4, P < 0.05), differed with CYP2B6*6 genotype and was affected by clopidogrel pretreatment (P < 0.05) but not by itraconazole pretreatment. CONCLUSIONS The disposition of 8,14-dihydroxy-EFV appears to be sensitive to CYP2B6 activity alterations in human subjects. The 8,14-dihydroxyefaviremz : efavirenz AUC(0,120 h) ratio is attractive as a candidate phenotyping index for CYP2B6 activity in vivo.