Flavonoid-Mediated Modulation of CYP3A Enzyme and P-Glycoprotein Transporter: Potential Effects on Bioavailability and Disposition of Tyrosine Kinase Inhibitors

Abstract

The consumption of herbal products and dietary supplements along with conventional medicines has raised concerns regarding herb-drug interactions. The available literature from experimental and clinical studies suggested that the consumption of herbs or dietary supplements that modulate efflux proteins, especially P-glycoprotein (P-gp) and metabolic enzyme CYP3A, may cause clinically relevant herb-drug interactions by alteration of bioavailability and disposition profiles of targeted drug. It has been also hypothesized that both CYP3A and P-gp work synergistically to limit systemic exposure of orally administered substrate drugs. Many in vitro and in vivo studies suggested that co-administration of flavonoids significantly enhances the bioavailability of orally administered drugs, which may be due to inhibition of the CYP3A enzyme and P-gp transporter. Recently, a large number of orally administered tyrosine kinase inhibitors (TKIs) have been clinically approved for cancer chemotherapy, and many are currently estimated to be under development. TKIs are all primarily metabolized by CYP3A, and most of them are also substrates of P-gp. Numerous studies have suggested that the plasma exposure of orally administered TKIs increases when co-administered with other drugs due to their dual inhibitory activities against P-gp and CYP3A. However, limited data are available regarding the interaction between flavonoids and TKIs. The objective of this article is to review the potential role of flavonoids in modulation of CYP3A enzyme and P-gp transporter and their influence on bioavailability and disposition of TKIs.