Genotype-phenotype associations for common CYP3A4 and CYP3A5 variants in the basal and induced metabolism of midazolam in European- and African-American men and women
Genotype-phenotype associations for common CYP3A4 and CYP3A5 variants in the basal and induced metabolism of midazolam in European- and African-American men and women
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DOI：
10.1097/00008571-200310000-00003
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发表时间：
2003-10-01
期刊：
影响因子：
--
通讯作者：
Wilkinson, GR
中科院分区：
文献类型：
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作者：
Floyd, MD;Gervasini, G;Wilkinson, GR
成人中的CYP 3A活性在个体之间存在差异，并且已经表明这具有遗传基础，可能与CYP 3A 4和CYP 3A 5基因中的变异等位基因有关。因此，在组成型和诱导条件下研究了基因型-表型关联。在57名健康受试者中测定咪达唑仑的全身和口服清除率以及红霉素呼吸试验（ERBT）：23名（11名男性，12名女性）欧洲人和34名（14名男性，20名女性）非洲裔美国人。研究在基础状态和利福平预处理14-15天后进行。通过直接测序对常见多态性CYP 3A 4 * 1B、CYP 3A 5 *3、CYP 3A 5 * 6和CYP 3A 5 * 7的DNA进行表征，并通过等位基因特异性实时聚合酶链反应对MDR 1的外显子21和外显子26变体进行表征。在95%的受试者中，咪达唑仑的基础全身清除率呈单峰分布，变异性小于4倍，而在98%的研究人群中，口服清除率变化5倍。没有明显的人群或性别相关差异，ERBT也观察到类似的结果。利福平预处理显著增加咪达唑仑的全身（2倍）和口服清除率（16倍），以及ERBT（2倍），但变异性不变。这些表型指标和任何研究的基因型之间没有相关性，除了口服利福平后的清除率及其倍数增加。这些与CYP 3A 4 * 1B和反向连锁的CYP 3A 5 *3多态性的存在相关，与野生型受试者相比，CYP 3A 5 *3纯合子的诱导程度约高50%。在大多数健康受试者中，使用咪达唑仑作为体内探针，肠道和肝脏CYP 3A活性的变异性是适度的，CYP 3A 4和CYP 3A 5中的常见多态性似乎没有重要的功能意义。药物遗传学（C）2003 Lippincott威廉姆斯威尔金斯。
CYP3A activity in adults varies between individuals and it has been suggested that this has a genetic basis, possibly related to variant alleles in CYP3A4 and CYP3A5 genes. Accordingly, genotype-phenotype associations were investigated under constitutive and induced conditions. Midazolam's systemic and oral clearances, and the erythromycin breath test (ERBT) were determined in 57 healthy subjects: 23 (11 men, 12 women) European- and 34 (14 men, 20 women) African-Americans. Studies were undertaken in the basal state and after 14-15 days pretreatment with rifampin. DNA was characterized for the common polymorphisms CYP3A4* 1B, CYP3A5*3, CYP3A5* 6 and CYP3A5* 7 by direct sequencing, and for exon 21 and exon 26 variants of MDR1 by allele-specific, real-time polymerase chain reaction. In 95% of subjects, the basal systemic clearance of midazolam was unimodally distributed and variability was less than fourfold whereas, in 98% of the study population, oral clearance varied five-fold. No population or sex-related differences were apparent Similar findings were observed with the ERBT. Rifampin pretreatment markedly increased the systemic (two-fold) and oral clearance (16-fold) of midazolam, and the ERBT (two-fold) but the variabilities were unchanged. No associations were noted between these phenotypic measures and any of the studied genotypes, except for oral clearance and its fold-increase after rifampin. These were related to the presence of CYP3A4* 1B and the inversely linked CYP3A5*3 polymorphism, with the extent of induction being approximately 50% greater in CYP3A5*3 homozygotes compared to wild-type subjects. In most healthy subjects, variability in intestinal and hepatic CYP3A activity, using midazolam as an in-vivo probe, is modest and common polymorphisms in CYP3A4 and CYP3A5 do not appear to have important functional significance. Pharmacogenetics (C) 2003 Lippincott Williams Wilkins.