CYP2B6, CYP2A6 and UGT2B7 genetic polymorphisms are predictors of efavirenz mid-dose concentration in HIV-infected patients.
CYP2B6, CYP2A6 and UGT2B7 genetic polymorphisms are predictors of efavirenz mid-dose concentration in HIV-infected patients.
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DOI：
10.1097/qad.0b013e3283319908
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发表时间：
2009-10-23
期刊：
影响因子：
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通讯作者：
Court MH
中科院分区：
文献类型：
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作者：
Kwara A;Lartey M;Sagoe KW;Kenu E;Court MH
udp -葡萄糖醛酸转移酶（UGT） 2B7最近被确定为介导依非韦伦n -葡萄糖醛酸化的主要酶。在这项研究中，我们确定了选择的UGT2B7多态性是否可以用来增强CYP2B6和CYP2A6基因型对依非韦伦血浆浓度的预测。在接受抗逆转录病毒治疗2-8周的94名hiv感染的加纳患者中，测定了中剂量依非韦伦的血浆浓度。CYP2B6和CYP2A6基因型此前已有报道。通过直接测序确定UGT2B7外显子2 snp c.735A>G （UGT2B7*1c; rs28365062）和c.802C>T (H268Y; UGT2B7*2; rs7439366)，将UGT2B7*1a定义为参考等位基因。通过单变量和多变量统计方法评估依非韦伦血浆浓度、人口统计学变量和基因型之间的关系。伊非韦伦中剂量血药浓度平均值（±SD）为3218（±3905）ng/mL，变异系数为121%。依非韦伦浓度的独立预测因子包括CYP2B6 c.516TT基因型（增加4,030 ng/mL, 95% CI, 2,882 ~ 5,505 ng/mL， P<0.001）、UGT2B7*1a携带者状态（增加475 ng/mL， 95% CI, 138 ~ 899 ng/mL， P=0.004）和CYP2A6*9和/或*17携带者状态（增加372 ng/mL， 95% CI, 74 ~ 742 ng/mL， P=0.013）。总体而言，CYP2B6 c.516TT基因型、UGT2B7*1a携带者状态和CYP2A6*9或*17携带者状态分别占总方差的45.2%、10.1%和8.6%。我们的研究结果表明，CYP2A6和UGT2B7遗传变异对依非韦伦配置的独立影响超出了CYP2B6多态性。用于估计依非韦伦适当剂量的药理学遗传算法的开发和测试应结合来自氧化和葡萄糖醛酸化途径的基因型数据。
UDP-glucuronosyltransferase (UGT) 2B7 was recently identified as the main enzyme mediating efavirenz N-glucuronidation. In this study we determined whether selected UGT2B7 polymorphisms could be used to enhance the prediction of efavirenz plasma concentrations from CYP2B6 and CYP2A6 genotypes. Mid-dose efavirenz plasma concentrations were determined in 94 HIV-infected Ghanaian patients at 2–8 weeks of antiretroviral therapy. CYP2B6 and CYP2A6 genotypes had been previously reported. UGT2B7 exon 2 SNPs c.735A>G (UGT2B7*1c; rs28365062) and c.802C>T (H268Y; UGT2B7*2; rs7439366) were determined by direct sequencing with UGT2B7*1a defined as the reference allele. Relationships between efavirenz plasma concentrations, demographic variables and genotypes were evaluated by univariate and multivariate statistical approaches. The mean (±SD) mid-dose efavirenz plasma concentration was 3218 (±3905) ng/mL with coefficient of variation of 121%. Independent predictors of efavirenz concentration included CYP2B6 c.516TT genotype (4,030 ng/mL increase; 95% CI, 2,882–5,505 ng/mL, P<0.001), UGT2B7*1a carrier status (475 ng/mL increase; 95% CI, 138–899 ng/mL, P=0.004) and CYP2A6*9 and/or *17 carrier status (372 ng/mL increase; 95% CI, 74–742 ng/mL, P=0.013). Overall, CYP2B6 c.516TT genotype, UGT2B7*1a carrier status and CYP2A6*9 or *17 carrier status accounted for 45.2%, 10.1%, and 8.6% of the total variance, respectively. Our findings demonstrate independent effects of CYP2A6 and UGT2B7 genetic variation on efavirenz disposition beyond that of the CYP2B6 polymorphisms. The development and testing of a pharmacogenetic algorithm for estimating the appropriate dose of efavirenz should incorporate genotypic data from both the oxidative and glucuronidation pathways.