Efavirenz Inhibits the Human Ether-A-Go-Go Related Current (hERG) and Induces QT Interval Prolongation in CYP2B6*6*6 Allele Carriers
Efavirenz Inhibits the Human Ether-A-Go-Go Related Current (hERG) and Induces QT Interval Prolongation in CYP2B6*6*6 Allele Carriers
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DOI：
10.1111/jce.13032
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发表时间：
2016-10-01
影响因子：
2.7
通讯作者：
Overholser, Brian R.
中科院分区：
文献类型：
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作者：
Abdelhady, Ahmed M.;Shugg, Tyler;Overholser, Brian R.
Efavirenz诱导QTc间期延长背景：尽管边际QT间期延长，defavirenz （EFV）仍与扭转点相关。由于EFV是由细胞色素P450 (CYP) 2B6酶代谢的，我们假设EFV会延长CYP2B6*6功能等位基因减少的携带者的率校正QT间期（QTcF）。目的本研究的主要目的是评估efv相关的QT间期变化与CYP2B6基因型的关系，并探讨QT间期延长的机制。方法健康志愿者（n = 57）单次给药600 mg，随后多次给药至稳定状态。对受试者进行已知CYP2B6等位基因的基因分型，并依次获得心电图和EFV血浆浓度。在CYP2B6表达和不表达的情况下，对稳定表达hERG和暴露于EFV的细胞进行全细胞电压钳实验。结果在CYP2B6*6/*6携带者中，fv表现出基因剂量效应，超过FDA QTcF间期延长标准。在CYP2B6*6/*6基因型中，QTcF在6小时（14毫秒，95% CI[1; 27]）、12小时（18毫秒，95% CI[-4; 40]）和18小时（6毫秒，95% CI[-1; 14]）时的平均时间匹配差异最大。EFV浓度超过0.4 g/mL显著抑制向外hERG尾电流（P < 0.05）。结论CYP2B6*6等位基因纯合子携带者可能通过抑制hERG而增加efv诱导QTcF间期延长的风险。
Efavirenz Induced QTc Interval ProlongationBackgroundEfavirenz (EFV) has been associated with torsade de pointes despite marginal QT interval lengthening. Since EFV is metabolized by the cytochrome P450 (CYP) 2B6 enzyme, we hypothesized that EFV would lengthen the rate-corrected QT (QTcF) interval in carriers of the CYP2B6*6 decreased functional allele.ObjectiveThe primary objective of this study was to evaluate EFV-associated QT interval changes with regard to CYP2B6 genotype and to explore mechanisms of QT interval lengthening.MethodsEFV was administered to healthy volunteers (n = 57) as a single 600 mg dose followed by multiple doses to steady-state. Subjects were genotyped for known CYP2B6 alleles and ECGs and EFV plasma concentrations were obtained serially. Whole-cell, voltage-clamp experiments were performed on cells stably expressing hERG and exposed to EFV in the presence and absence of CYP2B6 expression.ResultsEFV demonstrated a gene-dose effect and exceeded the FDA criteria for QTcF interval prolongation in CYP2B6*6/*6 carriers. The largest mean time-matched differences QTcF were observed at 6 hours (14 milliseconds; 95% CI [1; 27]), 12 hours (18 milliseconds; 95% CI [-4; 40]), and 18 hours (6 milliseconds; 95% CI [-1; 14]) in the CYP2B6*6/*6 genotype. EFV concentrations exceeding 0.4 g/mL significantly inhibited outward hERG tail currents (P < 0.05).ConclusionsThis study demonstrates that homozygous carriers of CYP2B6*6 allele may be at increased risk for EFV-induced QTcF interval prolongation via inhibition of hERG.