1] Division of Clinical Pharmacology, Department of Laboratory of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge C1-68, Stockholm, Sweden [2] Department of Pharmacology, Medical Faculty, Addis Ababa University, Addis Ababa, Ethiopia.
Pharmacogenomics J. 2013 Dec;13(6):484-9. doi: 10.1038/tpj.2012.46. Epub 2012 Oct 23.
We investigated the effects of pharmacogenetic variations and efavirenz pharmacokinetics on inter-individual differences in the extent of CYP3A induction by efavirenz using 4β-hydroxycholesterol/cholesterol (4β-OHC/Chol) as a marker for CYP3A induction. Plasma 4β-hydroxycholesterol and cholesterol concentrations were determined at baseline, and at the 4th, 16th and 48th week of efavirenz-based highly active antiretroviral therapy in antiretroviral therapy-naive HIV patients (n=77). Efavirenz plasma concentrations were quantified at weeks 4 and 16. CYP2B6, CYP3A5, ABCB1, UGT2B7 genotyping were done. Compared with baseline, the median plasma 4β-OHC/Chol ratio increased at the 4th (257%), 16th (291%) and 48th (165%) week (P<0.0001). CYP2B6*6 genotype significantly influenced 4β-OHC/Chol ratio at weeks 16 (P=0.02) and 48 (P=0.04) being highest in CYP2B6*6/*6>*1/*6>*1/*1. There were positive correlations between plasma efavirenz and 4β-OHC/Chol ratios (week 4: P=0.02, week 16: P=0.001). CYP3A enzyme induction by efavirenz is pronounced in CYP2B6 slow metabolizers who have high efavirenz plasma exposure.
我们使用 4β-羟胆固醇/胆固醇（4β-OHC/Chol）作为 CYP3A 诱导的标志物，研究了药物遗传学变异和依非韦伦药代动力学对依非韦伦诱导 CYP3A 程度的个体间差异的影响。在开始依非韦伦为基础的高效抗逆转录病毒治疗前（基线），以及在开始依非韦伦为基础的高效抗逆转录病毒治疗后的第 4、16 和 48 周，测定了未接受过抗病毒治疗的 HIV 患者的血浆 4β-羟胆固醇和胆固醇浓度。在第 4 和 16 周时定量测定了依非韦伦的血浆浓度。进行了 CYP2B6、CYP3A5、ABCB1、UGT2B7 基因分型。与基线相比，第 4、16 和 48 周时，血浆 4β-OHC/Chol 比值中位数分别增加了 257%、291%和 165%（P<0.0001）。CYP2B6*6 基因型显著影响第 16 周（P=0.02）和第 48 周（P=0.04）的 4β-OHC/Chol 比值，CYP2B6*6/*6>*1/*6>*1/*1 基因型的比值最高。血浆依非韦伦与 4β-OHC/Chol 比值呈正相关（第 4 周：P=0.02，第 16 周：P=0.001）。依非韦伦诱导的 CYP3A 酶在 CYP2B6 代谢缓慢的个体中明显增强，这些个体具有较高的依非韦伦血浆暴露量。
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