Ther Clin Risk Manag. 2005 Mar;1(1):3-13. doi: 10.2147/tcrm.1.1.3.53600.
Mechanism-based inhibition of cytochrome P450 (CYP) 3A4 is characterized by NADPH-, time-, and concentration-dependent enzyme inactivation, occurring when some drugs are converted by CYPs to reactive metabolites. Such inhibition of CYP3A4 can be due to the chemical modification of the heme, the protein, or both as a result of covalent binding of modified heme to the protein. The inactivation of CYP3A4 by drugs has important clinical significance as it metabolizes approximately 60% of therapeutic drugs, and its inhibition frequently causes unfavorable drug-drug interactions and toxicity. The clinical outcomes due to CYP3A4 inactivation depend on many factors associated with the enzyme, drugs, and patients. Clinical professionals should adopt proper approaches when using drugs that are mechanism-based CYP3A4 inhibitors. These include early identification of drugs behaving as CYP3A4 inactivators, rational use of such drugs (eg, safe drug combination regimen, dose adjustment, or discontinuation of therapy when toxic drug interactions occur), therapeutic drug monitoring, and predicting the risks for potential drug-drug interactions. A good understanding of CYP3A4 inactivation and proper clinical management are needed by clinical professionals when these drugs are used.
基于机制的细胞色素 P450（CYP）3A4 抑制的特征是 NADPH、时间和浓度依赖性酶失活，当某些药物被 CYP 转化为反应性代谢物时发生。CYP3A4 的这种抑制可能是由于血红素、蛋白质或两者的化学修饰，导致修饰的血红素与蛋白质发生共价结合。药物对 CYP3A4 的抑制具有重要的临床意义，因为它代谢了大约 60%的治疗药物，其抑制经常导致不良的药物相互作用和毒性。由于 CYP3A4 失活引起的临床后果取决于与酶、药物和患者相关的许多因素。临床专业人员在使用基于机制的 CYP3A4 抑制剂时应采用适当的方法。这些方法包括早期识别作为 CYP3A4 失活剂的药物、合理使用这些药物（例如，当发生毒性药物相互作用时，采用安全的药物联合方案、剂量调整或停止治疗）、治疗药物监测以及预测潜在药物相互作用的风险。当使用这些药物时，临床专业人员需要很好地理解 CYP3A4 失活和适当的临床管理。
