Efavirenz pharmacogenetics in a cohort of Italian patients
Efavirenz pharmacogenetics in a cohort of Italian patients
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DOI：
10.1016/j.ijantimicag.2015.11.012
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发表时间：
2016-02-01
影响因子：
10.8
通讯作者：
D'Avolio, Antonio
中科院分区：
文献类型：
--
作者：
Cusato, Jessica;Tomasello, Cristina;D'Avolio, Antonio
依法韦仑（EFV）的药物遗传学和药代动力学已被广泛研究，但意大利人群的数据有限。CYP 2B 6基因中的单核苷酸多态性（SNP）与EFV血浆浓度增加和中枢神经系统毒性相关。这项工作的目的是评估EFV血浆暴露根据SNPs参与药物代谢和消除的意大利HIV-1阳性患者接受EFV治疗的队列中的基因。使用经验证的HPLC/PDA系统，在摄入后12 h（C-12）使用血浆样品测量EFV浓度。使用全血通过实时PCR鉴定ABC 81、MRP 2、CYP 2B 6、CYP 2A 6、UGT 2B 7、NRII 2（PXR）、NRII 3（CAR）和HNF 4a中的SNP。通过非参数检验评估SNP与EFV血浆水平之间的关联。在201例患者中，中位EFV C12为2618.5 ng/mL。未发现MRP 2、CYP 2A 6、UGT 2B 7、PXR和CAR SNP的显著相关性;相反，观察到CYP 2B 6 51 6 G>T、A8 C813435 C>T和2677 G>T以及HNF 4a 975 C>G多态性与EFV C12相关。在多变量分析中，仅CYP 2B 6 516 TT和ABCB 1 3435 TT基因型与EFV C12>4000 ng/mL（毒性临界值）独立相关。本研究证实了CYP 2B 6和ABCB 1多态性的作用，显示了与HNF 4a的关系，以及CYP 2A 6、UGT 2B 7、NRII 2和NRII 3 SNP与EFV血浆暴露量之间缺乏关联。关于一些研究的SNP的数据是首次在意大利的HIV患者队列中获得的，并导致了关于EFV药物遗传学的全球视野。(C)2015年Elsevier B. V.和国际化疗学会。All rights reserved.
The pharmacogenetics and pharmacokinetics of efavirenz (EFV) have been widely studied, although data in the Italian population are limited. Single nucleotide polymorphisms (SNPs) in the CYP2B6 gene have been associated with increased EFV plasma concentrations and central nervous system toxicity. The aim of this work was to evaluate EFV plasma exposure according to SNPs in genes involved in drug metabolism and elimination in a cohort of Italian HIV-1-positive patients treated with EFV. Plasma samples were used to measure EFV concentrations at 12h after intake (C-12) by a validated HPLC/PDA system. Whole blood was used to identify SNPs in ABC81, MRP2, CYP2B6, CYP2A6, UGT2B7, NRII2 (PXR), NRII3 (CAR) and HNF4a by real-time PCR. The association between SNPs and EFV plasma levels was evaluated through non-parametric tests. Among 201 patients, the median EFV C12 was 2618.5 ng/mL. No significant associations were found for MRP2, CYP2A6, UGT2B7, PXR and CAR SNPs; conversely, an association of CYP2B6 51 6G>T,A8C813435C>T and 2677G>T, and HNF4a 975C>G polymorphisms with EFV C12 was observed. In multivariate analysis, only CYP2B6 516 TT and ABCB1 3435 TT genotypes were independently associated with an EFV C12 of >4000 ng/mL (toxicity cut-off). This study confirmed the role of CYP2B6 and ABCB1 polymorphisms, showed a relationship with HNF4a, and the lack of association of CYP2A6, UGT2B7, NRII2 and NRII3 SNPs on EFV plasma exposure. Data regarding some of the studied SNPs are the first obtained in an Italian cohort of HIV patients and lead to a global vision about EFV pharmacogenetics. (C) 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.