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.

Cytochrome P450 3A4 (CYP3A4), one of important members of the cytochrome P450 subfamily, acts as a critical catalyst for multiple drug metabolism. Pharmacological activities and clinical outcomes of CYP3A4-metabolized anticancer drugs greatly depend on this enzyme activity and expression, as it catalyzes a variety of reactions for drug activation or inactivation. In view of the complex tumor environments as well as various factors concerning CYP3A4 expression, function, and regulation such as physiological factors, disease complications, concomitant drugs, inflammation response and gene polymorphisms, the pharmacokinetics of most anticancer drugs are influenced by the degree of induction or inhibition CYP3A4 mediated metabolism. This inter-individual variability, together with the narrow therapeutic index of most anticancer drugs, therefore have important implications for achieving the expected efficacy and minimized toxicity from cancer chemotherapy in individuals. Goals of the review were to outline and discuss significant underlying factors that contribute to differences in drug metabolism in detail, including the expression, activity regulation and genotype of CYP3A4 in tumor tissues. The purpose is to highlight the clinically meaningful of CYP3A4 induction or inhibition for metabolic activation/inactivation-based cancer therapy. Assessing inter-individual variability of metabolic activity from multiple dimensions will facilitate the development of robust pharmacokinetics modeling approaches that may predict an individual’s CYP3A4-activated/deactivated drug metabolizing capacity and drug response, thereby selecting optimal treatment regimens.