Contributing factors on metabolic mechanism-based CYP3A4-activated/deactivated anticancer drugs: implications for individualizing chemotherapy

Abstract

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.