Pharmacogenetics and pharmacokinetics of CNS penetration of efavirenz and its metabolites
Pharmacogenetics and pharmacokinetics of CNS penetration of efavirenz and its metabolites
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DOI：
10.1093/jac/dky481
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发表时间：
2019-03-01
影响因子：
5.2
通讯作者：
Maartens, Gary
中科院分区：
文献类型：
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作者：
Decloedt, Eric H.;Sinxadi, Phumla Z.;Maartens, Gary
关于依非韦伦对中枢神经系统渗透的药物遗传学和药代动力学数据有限。目的研究与依非韦伦及其代谢物脑脊液浓度相关的遗传多态性，并探讨其与神经认知表现的关系。方法我们纳入了47名hiv感染的南非黑人成年人，有或没有hiv相关的神经认知障碍，服用依非韦伦/替诺福韦/恩曲他滨，并收集成对的血浆- csf样本。我们考虑了来自潜在相关基因（ABCC5、ABCG2、ABCB1、SLCO2B1、SCLO1A2、ABCC4、CYP2B6和CYP2A6）的2049个snp，包括已知影响血浆依非韦伦暴露的snp，其中880个符合连锁不平衡（LD）修剪阈值。结果鉴定出9种慢代谢、21种中间代谢和17种广泛代谢。多变量分析中CYP2B6 983基因型预测血浆efavirenz （=0.38， P=2.7x10(-03)）、血浆7-羟基-efavirenz （=0.59， P=3.7x10(-03)）、血浆8-羟基-efavirenz:efavirenz比值（=-0.31，P=1.8x10(-04)）和脑脊液efavirenz （=0.36， P=0.01）的log（10）转化浓度。血浆7-羟基-efavirenz浓度降低与CYP2A6 rs10853742 （=-0.55， P=3.5x10(-05)）、ABCB1 rs115780656 （=-0.65， P=4.1x10(-05)）、CYP2A6- 48ac （=-0.59， P=0.01）独立相关。CYP2A6-48AC与CSF 8-羟基-efavirenz:efavirenz比值升高独立相关（=0.54，P=0.048）。多因素分析显示，CYP2B6 rs2279345多态性与血浆7-羟基-依法韦伦：依法韦伦比值降低相关
Background There are limited data on the pharmacogenetics and pharmacokinetics of the CNS penetration of efavirenz.Objectives We investigated genetic polymorphisms associated with CSF concentrations of efavirenz and its metabolites and explored the relationships with neurocognitive performance.Methods We included 47 HIV-infected South African black adults with and without HIV-associated neurocognitive disorder on efavirenz/tenofovir/emtricitabine and collected paired plasma-CSF samples. We considered 2049 SNPs, including SNPs known to affect plasma efavirenz exposure, from potentially relevant genes (ABCC5, ABCG2, ABCB1, SLCO2B1, SCLO1A2, ABCC4, CYP2B6 and CYP2A6) and 880 met a linkage disequilibrium (LD)-pruning threshold.Results We identified 9 slow, 21 intermediate and 17 extensive metabolizers. The CYP2B6 983 genotype in multivariate analyses predicted log(10)-transformed concentrations of plasma efavirenz (=0.38, P=2.7x10(-03)), plasma 7-hydroxy-efavirenz (=0.59, P=3.7x10(-03)), plasma 8-hydroxy-efavirenz:efavirenz ratio (=-0.31, P=1.8x10(-04)) and CSF efavirenz (=0.36, P=0.01). Lower plasma 7-hydroxy-efavirenz concentrations were independently associated with CYP2A6 rs10853742 (=-0.55, P=3.5x10(-05)), ABCB1 rs115780656 (=-0.65, P=4.1x10(-05)) and CYP2A6-48AC (=-0.59, P=0.01). CYP2A6-48AC was independently associated with higher CSF 8-hydroxy-efavirenz:efavirenz ratio (=0.54, P=0.048). CYP2B6 rs2279345 polymorphism was associated with lower plasma 7-hydroxy-efavirenz:efavirenz ratio in multivariate analyses (P