Kumar Vikas, Wahlstrom Jan L, Rock Dan A, Warren Chad J, Gorman Lee A, Tracy Timothy S
Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA.
Drug Metab Dispos. 2006 Dec;34(12):1966-75. doi: 10.1124/dmd.106.010926. Epub 2006 Sep 8.
Drug-drug interactions may cause serious adverse events in the clinical setting, and the cytochromes P450 are the enzyme system most often implicated in these interactions. Cytochrome P450 2C is the second most abundant subfamily of cytochrome P450 enzymes and is responsible for metabolism of almost 20% of currently marketed drugs. The most abundant isoform of this subfamily is CYP2C9, which is the major clearance pathway for the low therapeutic index drugs warfarin and phenytoin. Considering the importance of CYP2C9 to drug-drug interactions, the in vitro-in vivo extrapolation of drug-drug interactions for CYP2C9 may be confounded by the presence of polymorphic variants and the possibility of multiple binding regions within the CYP2C9 active site, leading to the potential for genotype- and substrate-dependent inhibition. To address the issues of genotype-dependent enzyme inhibition as well as probe substrate correlations, the inhibitory potency (Ki) of 28 effector molecules was assessed with five commonly used probes of CYP2C9 in both the CYP2C9.1 and CYP2C9.3 proteins. The inhibition of CYP2C9.1 and CYP2C9.3 by the battery of inhibitors with five substrate probes demonstrated differential inhibition potency not only between the two genotypes but also across substrate probes. Furthermore, the substrate probes fell into three distinct classes depending on genotype, suggesting that multiple probes may be needed to fully assess inhibition of CYP2C9 in vitro. Thus, both genotype and choice of probe substrate must be considered when attempting to predict potential CYP2C9 drug-drug interactions from in vitro data.
药物相互作用可能在临床环境中导致严重不良事件，而细胞色素P450是最常涉及这些相互作用的酶系统。细胞色素P450 2C是细胞色素P450酶中含量第二丰富的亚家族，负责目前市场上近20%药物的代谢。该亚家族中最丰富的同工型是CYP2C9，它是低治疗指数药物华法林和苯妥英的主要清除途径。考虑到CYP2C9对药物相互作用的重要性，CYP2C9药物相互作用的体外-体内外推可能会因多态性变体的存在以及CYP2C9活性位点内多个结合区域的可能性而混淆，从而导致基因型和底物依赖性抑制的可能性。为了解决基因型依赖性酶抑制以及探针底物相关性的问题，在CYP2C9.1和CYP2C9.3蛋白中，用五种常用的CYP2C9探针评估了28种效应分子的抑制效力（Ki）。用五种底物探针组成的抑制剂对CYP2C9.1和CYP2C9.3的抑制作用不仅在两种基因型之间，而且在不同底物探针之间都表现出不同的抑制效力。此外，根据基因型，底物探针可分为三个不同的类别，这表明可能需要多种探针来全面评估体外CYP2C9的抑制作用。因此，在试图从体外数据预测潜在的CYP2C9药物相互作用时，必须考虑基因型和探针底物的选择。
