Stevens Jeffrey C
Pfizer Global Research and Development, 800 N. Lindbergh Blvd, Creve Coeur, MO 63167, USA.
Drug Discov Today. 2006 May;11(9-10):440-5. doi: 10.1016/j.drudis.2006.03.002.
Advances in the basic and clinical sciences of drug actions and safety have been applied almost exclusively to the largest demographic patient group--adults. Metabolism-dependent drug clearance is not only a primary determinant for obtaining efficacious drug exposure, but could also demonstrate clear age-dependence. These concepts are exemplified by the three major human cytochrome P450 (CYP) 3A enzymes: CYP3A4, CYP3A5 and CYP3A7. Recent preclinical and clinical studies show CYP3A7 is the most abundant CYP3A enzyme in fetal liver, with a gradual shift towards CYP3A4 expression throughout childhood. However, the polymorphic nature and regulatory intricacies of CYP3A5 and CYP3A7 expression could cause an underappreciated contribution to interindividual variability in drug response and safety.
药物作用与安全性的基础科学和临床科学进展几乎仅应用于最大的人口统计学患者群体——成年人。代谢依赖性药物清除不仅是获得有效药物暴露的主要决定因素，而且还可能表现出明显的年龄依赖性。这三个主要的人类细胞色素P450（CYP）3A酶：CYP3A4、CYP3A5和CYP3A7体现了这些概念。最近的临床前和临床研究表明，CYP3A7是胎儿肝脏中最丰富的CYP3A酶，在整个儿童期逐渐向CYP3A4表达转变。然而，CYP3A5和CYP3A7表达的多态性本质和调控复杂性可能导致对药物反应和安全性个体间差异的贡献未得到充分认识。
