CYP2C19 inhibition: The impact of substrate probe selection on in vitro inhibition profiles
CYP2C19 inhibition: The impact of substrate probe selection on in vitro inhibition profiles
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DOI：
10.1124/dmd.107.019265
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发表时间：
2008-03-01
影响因子：
3.9
通讯作者：
Wahlstrom, Jan L.
中科院分区：
文献类型：
--
作者：
Foti, Robert S.;Wahlstrom, Jan L.
了解细胞色素P450（P450）介导的药物相互作用的潜力是药物发现过程的关键部分。诸如非特异性结合、非典型动力学、效应物溶解度差和辅助蛋白的不同比例等因素可能会改变酶的动力学行为，并随后混淆体外数据外推至人体情况。P450活性位点的结构和活性位点内多个结合区域的存在也可能混淆体外-体内外推，因为抑制曲线可能依赖于特定的底物-底物相互作用。在这些研究中，根据最近美国的研究结果，对一组24种抑制剂的抑制特性进行了针对CYP 2C 19底物探针（S）-美芬妥英、（R）-奥美拉唑、（S）奥美拉唑和（S）-氟西汀的分组。S.美国食品药品监督管理局关于CYP 2C 19体外药物相互作用的指南。（S）-美芬妥英的抑制作用平均比（R）-或（S）-奥美拉唑强5.6倍，比（S）-氟西汀强9.2倍。抑制数据的分层聚类表明有三种底物探针分组，（S）-美芬妥英与其余底物探针的差异最大，（S）-氟西汀与（S）-美芬妥英和奥美拉唑的差异较小，（R）-和（S）-奥美拉唑彼此之间的差异最小。基于体外数据的体内抑制效力预测表明，大多数药物-药物相互作用将通过（S）-美芬妥英或奥美拉唑鉴别，尽管相互作用的预期幅度可能因所选底物探针而异。
Understanding the potential for cytochrome P450 (P450)-mediated drug-drug interactions is a critical part of the drug discovery process. Factors such as nonspecific binding, atypical kinetics, poor effector solubility, and varying ratios of accessory proteins may alter the kinetic behavior of an enzyme and subsequently confound the extrapolation of in vitro data to the human situation. The architecture of the P450 active site and the presence of multiple binding regions within the active site may also confound in vitro-in vivo extrapolation, as inhibition profiles may be dependent on a specific inhibitor-substrate interaction. In these studies, the inhibition profiles of a set of 24 inhibitors were paneled against the CYP2C19 substrate probes (S)-mephenytoin, (R)-omeprazole, (S)omeprazole, and (S)-fluoxetine, on the basis of their inclusion in recent U. S. Food and Drug Administration guidance for in vitro drug-drug interactions with CYP2C19. (S)-Mephenytoin was inhibited an average of 5.6-fold more potently than (R)-or (S)-omeprazole and 9.2-fold more potently than (S)-fluoxetine. Hierarchical clustering of the inhibition data suggested three substrate probe groupings, with (S)-mephenytoin exhibiting the largest difference from the rest of the substrate probes, (S)-fluoxetine exhibiting less difference from (S)-mephenytoin and the omeprazoles and (R)-and (S)-omeprazole exhibiting minimal differences from each other. Predictions of in vivo inhibition potency based on the in vitro data suggest that most drug-drug interactions will be identified by either (S)-mephenytoin or omeprazole, although the expected magnitude of the interaction may vary depending on the chosen substrate probe.