CYP3A4 激活/灭活抗癌药物：个体化癌症治疗的影响因素,Drug Metabolism and Disposition

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CYP3A4 激活/灭活抗癌药物：个体化癌症治疗的影响因素
Drug Metabolism and Disposition ( IF 4.4 ) Pub Date : 2023-05-01 , DOI: 10.1124/dmd.122.001131
Fengling Wang ₁ , Xue Zhang ₂ , Yanyan Wang ₂ , Yunna Chen ₂ , Huiyu Lu ₂ , Xiangyun Meng ₂ , Xi Ye ₂ , Weidong Chen ₁

Affiliation

细胞色素 P450 3A4 (CYP3A4) 是细胞色素 P450 亚家族中最重要的成员之一，是许多药物代谢的重要催化剂。由于它催化许多药物激活或失活过程，因此由 CYP3A4 代谢的抗癌药物的药理活性和临床结果高度依赖于该酶的活性和表达。由于肿瘤微环境的复杂性以及在人体体外模型和临床研究中观察到的各种影响因素，大多数抗癌药物的药代动力学受到诱导或抑制 CYP3A4 介导代谢的程度的影响，而这些细节并未得到充分认识和突出显示。因此，这种由遗传和非遗传因素引起的个体差异，再加上大多数抗癌药物的治疗指数较窄，导致了它们独特的暴露和反应，这对于实现预期疗效和最大限度地减少个体癌症化疗的不良事件具有重要意义。为了阐明与个性化治疗相关的 CYP3A4 介导的抗癌药物激活/失活的机制，这篇综述重点关注导致 CYP3A4 代谢活性差异的潜在决定因素，并对这些因素的重要性提供了全面而有价值的概述，这些因素不同从目前对癌症治疗给药方案的考虑。我们还讨论了知识差距、挑战和机会，以探索个体患者药物代谢激活/失活的最佳给药方案，

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Activation/Inactivation of Anticancer Drugs by CYP3A4: Influencing Factors for Personalized Cancer Therapy

Cytochrome P450 3A4 (CYP3A4), one of the most important members of the cytochrome P450 subfamily, is a crucial catalyst in the metabolism of numerous drugs. As it catalyzes numerous processes for drug activation or inactivation, the pharmacological activities and clinical outcomes of anticancer drugs metabolized by CYP3A4 are highly dependent on the enzyme’s activity and expression. Due to the complexity of tumor microenvironments and various influencing factors observed in human in vitro models and clinical studies, the pharmacokinetics of most anticancer drugs are influenced by the extent of induction or inhibition of CYP3A4-mediated metabolism, and these details are not fully recognized and highlighted. Therefore, this interindividual variability due to genetic and nongenetic factors, together with the narrow therapeutic index of most anticancer drugs, contributes to their unique set of exposures and responses, which have important implications for achieving the expected efficacy and minimizing adverse events of chemotherapy for cancer in individuals. To elucidate the mechanisms of CYP3A4-mediated activation/inactivation of anticancer drugs associated with personalized therapy, this review focuses on the underlying determinants that contribute to differences in CYP3A4 metabolic activity and provides a comprehensive and valuable overview of the significance of these factors, which differs from current considerations for dosing regimens in cancer therapy. We also discuss knowledge gaps, challenges, and opportunities to explore optimal dosing regimens for drug metabolic activation/inactivation in individual patients, with particular emphasis on pooling and analyzing clinical information that affects CYP3A4 activity.

更新日期：2023-04-27

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