Wang Fengling, Zhang Xue, Wang Yanyan, Chen Yunna, Lu Huiyu, Meng Xiangyun, Ye Xi, Chen Weidong
Department of Pharmacy, Hefei Hospital, Affiliated to Anhui Medical University (The Second People's Hospital of Hefei), Hefei, Anhui, China (F.W., X.M., X.Y.); School of Pharmacy, Anhui Medical University, Hefei, Anhui, China (F.W.); School of Pharmacy (F.W., X.Z., Y.W., Y.C., H.L., W.C.) and Institute of Pharmaceutics, School of Pharmaceutical Sciences (X.Z., H.L., W.C.), Anhui University of Chinese Medicine, Hefei, Anhui, China; The Second People's Hospital of Hefei, Affiliated to Bengbu Medical College, Hefei, Anhui, China (F.W., X.M., X.Y.); and MOE-Anhui Joint Collaborative Innovation Center for Quality Improvement of Anhui Genuine Chinese Medicinal Materials, Hefei, Anhui, China (W.C.)
Department of Pharmacy, Hefei Hospital, Affiliated to Anhui Medical University (The Second People's Hospital of Hefei), Hefei, Anhui, China (F.W., X.M., X.Y.); School of Pharmacy, Anhui Medical University, Hefei, Anhui, China (F.W.); School of Pharmacy (F.W., X.Z., Y.W., Y.C., H.L., W.C.) and Institute of Pharmaceutics, School of Pharmaceutical Sciences (X.Z., H.L., W.C.), Anhui University of Chinese Medicine, Hefei, Anhui, China; The Second People's Hospital of Hefei, Affiliated to Bengbu Medical College, Hefei, Anhui, China (F.W., X.M., X.Y.); and MOE-Anhui Joint Collaborative Innovation Center for Quality Improvement of Anhui Genuine Chinese Medicinal Materials, Hefei, Anhui, China (W.C.).
Drug Metab Dispos. 2023 May;51(5):543-559. doi: 10.1124/dmd.122.001131. Epub 2023 Feb 2.
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. SIGNIFICANCE STATEMENT: This review focuses on anticancer drugs that are activated/deactivated by CYP3A4 and highlights outstanding factors affecting the interindividual variability of CYP3A4 activity in order to gain a detailed understanding of CYP3A4-mediated drug metabolism mechanisms. A systematic analysis of available information on the underlying genetic and nongenetic determinants leading to variation in CYP3A4 metabolic activity to predict therapeutic response to drug exposure, maximize efficacy, and avoid unpredictable adverse events has clinical implications for the identification and development of CYP3A4-targeted cancer therapeutics.
细胞色素P450 3A4（CYP3A4）是细胞色素P450亚家族最重要的成员之一，是众多药物代谢中的关键催化剂。由于它催化药物活化或失活的众多过程，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类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CYP3A4介导的代谢诱导或抑制程度的影响，而这些细节尚未得到充分认识和强调。因此，由于遗传和非遗传因素导致的个体间变异性，以及大多数抗癌药物狭窄的治疗指数，促成了它们独特的暴露和反应模式，这对于在个体中实现预期疗效并将癌症化疗的不良事件降至最低具有重要意义。为了阐明与个性化治疗相关的CYP3A4介导的抗癌药物活化/失活机制，本综述重点关注导致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全面且有价值的概述，这与目前癌症治疗给药方案的考虑不同。我们还讨论了知识空白、挑战以及探索个体患者药物代谢活化/失活最佳给药方案的机会，特别强调汇总和分析影响CYP3A4活性的临床信息。意义声明：本综述聚焦于由CYP3A4活化/失活的抗癌药物，并突出影响CYP3A4活性个体间变异性的突出因素，以便深入了解CYP3A4介导的药物代谢机制。对导致CYP3A4代谢活性变化的潜在遗传和非遗传决定因素的现有信息进行系统分析，以预测药物暴露的治疗反应、最大化疗效并避免不可预测的不良事件，对CYP3A4靶向癌症治疗药物的识别和开发具有临床意义。
