Department of Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, Cambridge, MA USA.
Curr Top Med Chem. 2011;11(4):382-403. doi: 10.2174/156802611794480882.
Evaluation of the potential of a drug candidate to inhibit or inactivate cytochrome P450 (CYP) enzymes remains an important part of pharmaceutical drug Discovery and Development programs. CYP enzymes are considered to be one of the most important enzyme families involved in the metabolic clearance of the vast majority of prescribed drugs. Clinical drug-drug interactions (DDI) involving inhibition or time-dependent inactivation of these enzymes can result in dangerous side effects resulting from reduced clearance/increased exposure of the drug being affected (the 'victim' drug). In this regard, pharmaceutical companies have become quite vigilant in mitigating CYP inhibition/inactivation liabilities of drug candidates early in Discovery including continued risk assessment throughout Development. In this review, common strategies and decision making processes for the assessment of DDI risk in the different stages of pharmaceutical development are discussed. In addition, in vitro study designs, analysis, and interpretation of CYP inhibition and inactivation data are described in stage appropriate context. The in vitro tools and knowledge available now enable the Discovery Chemist to place the potential CYP DDI liability of a drug candidate into perspective and to aid in the optimization of chemical drug design to further mitigate this risk.
评估候选药物抑制或失活细胞色素 P450（CYP）酶的潜力仍然是药物发现和开发计划的重要组成部分。CYP 酶被认为是参与代谢清除绝大多数处方药物的最重要的酶家族之一。涉及这些酶的抑制或时间依赖性失活的临床药物-药物相互作用（DDI）可能导致受影响药物（“受害者”药物）清除/暴露增加导致的危险副作用。在这方面，制药公司在发现阶段就非常警惕候选药物的 CYP 抑制/失活的潜在风险，并在整个开发过程中持续进行风险评估。在这篇综述中，讨论了在药物开发的不同阶段评估 DDI 风险的常见策略和决策过程。此外，还描述了在适当阶段背景下进行 CYP 抑制和失活数据的体外研究设计、分析和解释。现在可用的体外工具和知识使发现化学家能够正确看待候选药物的潜在 CYP DDI 责任，并有助于优化化学药物设计以进一步降低这种风险。
