依非韦伦及其代谢物透过血脑屏障的药物遗传学和药代动力学。
Pharmacogenetics and pharmacokinetics of CNS penetration of efavirenz and its metabolites.
机构信息
Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
出版信息
J Antimicrob Chemother. 2019 Mar 1;74(3):699-709. doi: 10.1093/jac/dky481.
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 log10-transformed concentrations of plasma efavirenz (β = 0.38, P = 2.7 × 10-03), plasma 7-hydroxy-efavirenz (β = 0.59, P = 3.7 × 10-03), plasma 8-hydroxy-efavirenz:efavirenz ratio (β = -0.31, P = 1.8 × 10-04) and CSF efavirenz (β = 0.36, P = 0.01). Lower plasma 7-hydroxy-efavirenz concentrations were independently associated with CYP2A6 rs10853742 (β = -0.55, P = 3.5 × 10-05), ABCB1 rs115780656 (β = -0.65, P = 4.1 × 10-05) and CYP2A6 -48A→C (β = -0.59, P = 0.01). CYP2A6 -48A→C was independently associated with higher CSF 8-hydroxy-efavirenz:efavirenz ratio (β = 0.54, P = 0.048). CYP2B6 rs2279345 polymorphism was associated with lower plasma 7-hydroxy-efavirenz:efavirenz ratio in multivariate analyses (P < 0.05). No polymorphisms were associated with CSF:plasma ratios of efavirenz, plasma or CSF concentrations of 8-hydroxy-efavirenz or neurocognitive performance.
CONCLUSIONS
We identified novel genetic associations with plasma efavirenz, plasma 7-hydroxy-efavirenz, plasma 7-hydroxy-efavirenz:efavirenz ratio, plasma 8-hydroxy-efavirenz:efavirenz ratio, CSF efavirenz and CSF 8-hydroxy-efavirenz:efavirenz ratio.
背景
埃替拉韦在中枢神经系统中的药物代谢动力学和药物遗传学方面的数据有限。
目的
我们研究了与埃替拉韦脑脊液浓度相关的遗传多态性，并探讨了其与神经认知功能的关系。
方法
我们纳入了 47 名接受依非韦伦/替诺福韦/恩曲他滨治疗的南非黑人艾滋病毒感染者，包括有和无艾滋病毒相关的神经认知障碍者，并收集了配对的血浆-脑脊液样本。我们考虑了 2049 个 SNP，包括已知影响血浆埃替拉韦暴露的 SNP，来自潜在相关的基因（ABCC5、ABCG2、ABCB1、SLCO2B1、SCLO1A2、ABCC4、CYP2B6 和 CYP2A6）和 880 个符合连锁不平衡（LD）修剪阈值的 SNP。
结果
我们确定了 9 名慢代谢者、21 名中速代谢者和 17 名快速代谢者。多变量分析中 CYP2B6 983 基因型预测了血浆埃替拉韦（β=0.38，P=2.7×10-03）、血浆 7-羟基-埃替拉韦（β=0.59，P=3.7×10-03）、血浆 8-羟基-埃替拉韦：埃替拉韦比值（β=-0.31，P=1.8×10-04）和脑脊液埃替拉韦（β=0.36，P=0.01）的对数转化浓度。较低的血浆 7-羟基-埃替拉韦浓度与 CYP2A6 rs10853742（β=-0.55，P=3.5×10-05）、ABCB1 rs115780656（β=-0.65，P=4.1×10-05）和 CYP2A6-48A→C（β=-0.59，P=0.01）独立相关。CYP2A6-48A→C 与脑脊液中 8-羟基-埃替拉韦：埃替拉韦比值升高独立相关（β=0.54，P=0.048）。CYP2B6 rs2279345 多态性与多变量分析中血浆 7-羟基-埃替拉韦：埃替拉韦比值降低相关（P<0.05）。没有多态性与脑脊液：血浆埃替拉韦比值、血浆或脑脊液中 8-羟基-埃替拉韦浓度或神经认知功能相关。
结论
我们发现了与血浆埃替拉韦、血浆 7-羟基-埃替拉韦、血浆 7-羟基-埃替拉韦：埃替拉韦比值、血浆 8-羟基-埃替拉韦：埃替拉韦比值、脑脊液埃替拉韦和脑脊液 8-羟基-埃替拉韦：埃替拉韦比值相关的新的遗传关联。
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