细胞色素P450 2B6（c.516G→T）和细胞色素P450 2A6（*9B和/或*17）基因多态性是HIV感染患者中依非韦伦血浆浓度的独立预测指标。
CYP2B6 (c.516G-->T) and CYP2A6 (*9B and/or *17) polymorphisms are independent predictors of efavirenz plasma concentrations in HIV-infected patients.
作者信息
Kwara Awewura, Lartey Margaret, Sagoe Kwamena W, Rzek Naser L, Court Michael H
机构信息
The Miriam Hospital, Providence, RI 02906, USA.
出版信息
Br J Clin Pharmacol. 2009 Apr;67(4):427-36. doi: 10.1111/j.1365-2125.2009.03368.x.
AIMS
Interindividual variability in efavirenz pharmacokinetics is not entirely explained by the well-recognized CYP2B6 516G-->T single nucleotide polymorphism. The aim of this study was to determine whether polymorphisms in the CYP2A6 gene can be used to enhance the predictability of efavirenz concentrations in human immunodeficiency virus (HIV)-infected native African patients.
METHODS
Mid-dose efavirenz plasma concentrations were determined at 4 and 8 weeks following initiation of antiretroviral therapy in 65 HIV-infected Ghanaian patients. Selected CYP2B6 and CYP2A6 genotypes were determined by commercial 5'-nuclease assays. Relationships between averaged 4- and 8-week mid-dose efavirenz concentrations, demographic variables and genotypes were evaluated by univariate and multivariate statistical approaches including gene-gene interactions.
RESULTS
CYP2B6 c.516G-->T, CYP2B6 c.983T-->C, CYP2A69B and CYP2A617 allele frequencies were 45, 4, 5 and 12%, respectively. Rifampicin therapy, gender, age and body mass index had no significant influence on efavirenz mid-dose concentrations. Median efavirenz concentrations were more than five times higher (P < 0.001) in patients with CYP2B6 c.516TT genotype compared with GG and GT genotypes. Although none of the CYP2A6 genotypes was associated with altered efavirenz concentrations individually, CYP2A6*9B and/or CYP2A6*17 carriers showed a 1.8 times higher median efavirenz concentration (P= 0.017) compared with noncarriers. Multiple linear regression analysis indicated that the CYP2B6 c.516G-->T polymorphism and CYP2A6 slow-metabolizing variants accounted for as much as 36 and 12% of the total variance in efavirenz concentrations, respectively.
CONCLUSIONS
Our findings support previous work showing efavirenz oxidation by CYP2A6, and suggest that both CYP2A6 and CYP2B6 genotyping may be useful for predicting efavirenz plasma concentrations.
目的
依非韦伦药代动力学的个体间差异不能完全由已得到充分认识的CYP2B6 516G→T单核苷酸多态性来解释。本研究的目的是确定CYP2A6基因多态性是否可用于提高对感染人类免疫缺陷病毒（HIV）的非洲本土患者体内依非韦伦浓度的预测能力。
方法
在65例感染HIV的加纳患者开始抗逆转录病毒治疗后的第4周和第8周，测定中剂量依非韦伦的血浆浓度。通过商业5′-核酸酶分析确定选定的CYP2B6和CYP2A6基因型。采用单变量和多变量统计方法（包括基因-基因相互作用）评估第4周和第8周的平均中剂量依非韦伦浓度、人口统计学变量和基因型之间的关系。
结果
CYP2B6 c.516G→T、CYP2B6 c.983T→C、CYP2A69B和CYP2A617等位基因频率分别为45%、4%、5%和12%。利福平治疗、性别、年龄和体重指数对依非韦伦中剂量浓度无显著影响。与GG和GT基因型患者相比，CYP2B6 c.516TT基因型患者的依非韦伦中位浓度高出五倍多（P<0.001）。虽然单独的CYP2A6基因型均与依非韦伦浓度改变无关，但与非携带者相比，CYP2A69B和/或CYP2A617携带者的依非韦伦中位浓度高1.8倍（P = 0.017）。多元线性回归分析表明，CYP2B6 c.516G→T多态性和CYP2A6慢代谢变体分别占依非韦伦浓度总变异的36%和12%。
结论
我们的研究结果支持先前关于CYP2A6对依非韦伦氧化作用的研究工作，并表明CYP2A6和CYP2B6基因分型均可能有助于预测依非韦伦的血浆浓度。
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