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 micro -environments 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 re-sponses, which have important implications for achieving the expected efficacy and minimizing adverse events of chemotherapy for cancer in in-dividuals. 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 dif ferences 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 indi-vidual patients, with particular emphasis on pooling and analyzing clinical information that affects CYP3A4 activity.

Automated summary

Cytochrome P450 3A4 (CYP3A4) plays a crucial role in the metabolism of many drugs, especially anticancer drugs. The activity and expression of CYP3A4 greatly affect the pharmacological activities and clinical outcomes of these drugs. However, there is still limited understanding of the factors influencing CYP3A4-mediated drug metabolism, leading to interindividual variability and potential adverse events. This review focuses on elucidating the underlying determinants of CYP3A4 activity and discusses the challenges and opportunities for optimizing dosing regimens in personalized cancer therapy.