Strategies to overcome simultaneous P-glycoprotein mediated efflux and CYP3A4 mediated metabolism of drugs

Cytochrome P450 3A4 (CYP3A4), abundant in both the liver and upper intestinal enterocytes, limits the systemic bioavailability of xenobiotics. P-glycoprotein (P-gp), the MDR1 gene product, is also known to reduce the oral bioavailability of the drug molecules. High cellular expression of P-gp and CYP3A4 in mature intestinal enterocytes and their similar substrate specificity suggest that the function of these proteins may be complementary and may form a co-ordinated intestinal barrier. Various ongoing preclinical and clinical studies have demonstrated that the oral bioavailability of various P-gp and/or CYP3A4 substrates can be increased by simultaneous administration of P-gp and/or CYP3A4 inactivators. The current review describes the background and summarises several proposed hypotheses in modifying oral bioavailability by various drug-inhibitor interactions.