Drug-drug interactions (DDI) and genomic variation (PG) can lead to dangerously high blood and tissue concentrations with some drugs but may be negligible with other drugs. Using a quantitative metaanalysis, we analyzed on the example of CYP2D6 and CYP2C19 substrates, how well the effects of DDI and PG can be predicted by in vitro methods. In addition, we analyzed the quantitative effect of prototypic inhibitors of the two enzymes in relation to their genetic deficiency. More than 600 published studies were screened which compared either human pharmacokinetics with and without comedication, or which compared human pharmacokinetics of deficient with extensive metabolizers, or which assessed metabolism by in vitro approaches. With human liver microsomes, the in vitro to in vivo agreement of fractional clearances was reasonably high if loss of substrate was quantified in the in vitro assays performed with and without enzyme specific inhibitors. Also a generally very high correlation between the clinical pharmacokinetic effects of inherited deficiency and inhibition by drug-drug interactions could be demonstrated. Most cases of poor correlation were explained by the lack of CYP2D6 versus CYP2C19 specificity of fluoxetine or by a poor knowledge of the quantitative contribution of the metabolic pathways if metabolite formation was quantified in the in vitro assays. The good correspondence of the in vitro data with clinical DDI and clinical PG studies may be a good basis for future application of these methods in drug development and drug therapy.

药物间相互作用 (DDI) 和基因组变异 (PG) 可能会导致某些药物的血液和组织浓度达到危险的高水平，但对于其他药物则可能可以忽略不计。通过定量荟萃分析，我们以 CYP2D6 和 CYP2C19 底物为例，分析了通过体外方法预测 DDI 和 PG 的效果的效果。此外，我们还分析了这两种酶的原型抑制剂与其遗传缺陷相关的定量效应。筛选了 600 多项已发表的研究，这些研究比较了有或没有药物治疗的人体药代动力学，或者比较了缺乏药物和强代谢物的人体药代动力学，或者通过体外方法评估了代谢。对于人肝微粒体，如果在使用和不使用酶特异性抑制剂进行的体外测定中对底物的损失进行定量，则体外与体内清除率分数的一致性相当高。还可以证明遗传性缺陷的临床药代动力学效应与药物间相互作用的抑制之间通常具有非常高的相关性。大多数相关性较差的情况是由于氟西汀缺乏 CYP2D6 与 CYP2C19 特异性，或者如果在体外测定中量化代谢物形成，则对代谢途径的定量贡献了解不足。体外数据与临床DDI和临床PG研究的良好对应性可能为这些方法未来在药物开发和药物治疗中的应用奠定良好的基础。