Miao J, Jin Y, Marunde R L, Gorski C J, Kim S, Quinney S, Radovich M, Li L, Hall S D
Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Pharmacogenomics J. 2009 Oct;9(5):319-26. doi: 10.1038/tpj.2009.21. Epub 2009 Jun 9.
The genes that encode for CYP3A4 and CYP3A5 are located in the same region (CYP3A cluster) on chromosome 7. Midazolam (MDZ) is a substrate for both CYP3A4 and CYP3A5. We hypothesize that MDZ disposition in vivo is associated with genotypes of the CYP3A cluster. A meta-analysis of the pharmacokinetic (PK) parameters from seven clinical trials was carried out, in which MDZ was administered both intravenously and orally. DNA samples were available from 116 patients. There were significant ethnic differences in the allelic frequencies of these four common single-nucleotide polymorphisms (SNPs) in the CYP3A cluster. Significant linkage disequilibrium was found between CYP3A5()3 and CYP3A4()1A in Caucasians, and between CYP3A5()1 and CYP3A4()1B in African Americans. There were no differences in MDZ disposition in vivo between different genotypes, haplotypes and diplotypes in the CYP3A cluster (P>0.05). No significant differences in MDZ PK parameters were observed between Caucasians and African Americans. Women had higher weight-corrected systemic and oral clearance than men, but dose-adjusted AUC and bioavailability differences were not observed between sexes. The clinical importance of elevated CYP3A activity in women remains to be determined. The r(GC)'s of MDZ PK parameters were between 0.3 and 13.6%. In conclusion, the meta-analysis of seven studies suggests that environmental factors explain the majority of CYP3A activity variation. Further studies are necessary to define the functional significance of SNPs in the CYP3A cluster and the effects of CYP3A genotypes on MDZ disposition in vivo.
编码CYP3A4和CYP3A5的基因位于7号染色体的同一区域（CYP3A基因簇）。咪达唑仑（MDZ）是CYP3A4和CYP3A5的底物。我们推测MDZ在体内的处置与CYP3A基因簇的基因型有关。对七项临床试验的药代动力学（PK）参数进行了荟萃分析，其中MDZ通过静脉和口服给药。从116名患者中获取了DNA样本。CYP3A基因簇中这四种常见单核苷酸多态性（SNP）的等位基因频率存在显著的种族差异。在白种人中，CYP3A5（）3和CYP3A4（）1A之间存在显著的连锁不平衡，在非裔美国人中，CYP3A5（）1和CYP3A4（）1B之间存在显著的连锁不平衡。CYP3A基因簇中不同基因型、单倍型和双倍型之间在MDZ体内处置方面没有差异（P>0.05）。白种人和非裔美国人之间在MDZ的PK参数上没有观察到显著差异。女性的体重校正全身清除率和口服清除率高于男性，但在性别之间未观察到剂量调整后的AUC和生物利用度差异。女性中CYP3A活性升高的临床重要性仍有待确定。MDZ PK参数的r（GC）在0.3%至13.6%之间。总之，对七项研究的荟萃分析表明，环境因素解释了CYP3A活性变异的大部分原因。有必要进一步研究以确定CYP3A基因簇中SNP的功能意义以及CYP3A基因型对MDZ体内处置的影响。
