Louvain Centre for Toxicology & Applied Pharmacology, Université Catholique de Louvain, 53.02, Avenue E. Mounier, 1200 Bruxelles, Belgium.
Pharmacogenomics. 2010 Sep;11(9):1223-34. doi: 10.2217/pgs.10.94.
Efavirenz (EFV) is characterized by interindividual pharmacokinetic variability causing inconsistent clinical responses. Previous studies have identified some possible genetic determinants of the variability in plasma concentrations. However, their impact on EFV intracellular pharmacokinetics remains mostly unexplored.
To confirm previous observations concerning the influence of genetic polymorphisms on EFV plasma concentrations and to assess their effect on the intracellular pharmacokinetics of EFV.
MATERIALS & METHODS: EFV concentrations in plasma (EFV) and in peripheral blood mononuclear cells (EFV) were determined in 50 HIV-infected patients. Subjects were genotyped for 13 polymorphisms in 5 different genes (CYP2A6, CYP2B6, CYP3A5, UGT2B7 and ABCB1). Relationships between genetic status and EFV, EFV or EFV accumulation in peripheral blood mononuclear cells (EFV accumulation ratio or accumulation ration [AR]) were then evaluated.
CYP2B6 allelic status was associated with differences in EFV but also in EFV. Patients carrying at least one mutated allele showed significantly higher EFV and EFV than homozygous wild-type (mutated homozygous [m/m] >heterozygous [wt/m]>homozygous wild-type [wt/wt], p<0.001). ABCB1 rs3842T>C was significantly associated with higher EFV AR (p = 0.032). Finally, the ABCB1 3435C>T SNP was associated with a lower increase in CD4-cell count after EFV therapy initiation.
Our study corroborates previous findings indicating that knowledge of CYP2B6 genetic status should be taken into account for an EFV treatment. Our results also constitute the first demonstration of the significant influence of CYP2B6 genetic polymorphisms on EFV and suggest that ABCB1 SNPs may also influence the clinical impact of EFV treatment.
依非韦伦（EFV）的药代动力学个体间存在差异，导致临床反应不一致。先前的研究已经确定了一些可能影响血浆浓度变异性的遗传决定因素。然而，它们对 EFV 细胞内药代动力学的影响在很大程度上仍未得到探索。
确认先前关于遗传多态性对 EFV 血浆浓度影响的观察结果，并评估其对 EFV 细胞内药代动力学的影响。
对 50 名感染 HIV 的患者进行了血浆中 EFV 浓度 (EFV) 和外周血单个核细胞中 EFV 浓度 (EFV) 的测定。对 5 个不同基因（CYP2A6、CYP2B6、CYP3A5、UGT2B7 和 ABCB1）的 13 个多态性进行了基因分型。然后评估了遗传状态与 EFV、EFV 或外周血单个核细胞中 EFV 积累（EFV 积累比或积累比 [AR]）之间的关系。
CYP2B6 等位基因状态与 EFV 差异有关，但也与 EFV 差异有关。携带至少一个突变等位基因的患者的 EFV 和 EFV 明显高于纯合野生型（突变纯合型 [m/m] >杂合型 [wt/m]>纯合野生型 [wt/wt]，p<0.001）。ABCB1 rs3842T>C 与较高的 EFV AR 显著相关（p=0.032）。此外，ABCB1 3435C>T SNP 与 EFV 治疗开始后 CD4 细胞计数的增加幅度较低有关。
本研究证实了先前的发现，即 CYP2B6 遗传状态的知识应考虑用于 EFV 治疗。我们的结果还首次表明 CYP2B6 遗传多态性对 EFV 有显著影响，并提示 ABCB1 SNP 也可能影响 EFV 治疗的临床效果。
