The intestinal cytochrome P450 3A and P-glycoprotein:barriers to drug absorption

Cytochrome P450 3A (CYP3A/CYP3A4), the major phase I drug metabolizing enzyme in humans, and the Mdr1 gene expressed P glycoprotein (P gp), the drug efflux pump, are present at high levels in the villus tip of enterocytes of gastrointestinal tract, the primary site of absorption for orally administrated drugs, and share a significant overlap in substrate specificity. It has been recognized that metabolism by intestinal CYP3A/CYP3A4 is one of the major determinants of oral drug bioavailability. More recently, a large quantity of research has demonstrated that drug extrusion by intestinal P gp can both reduce drug absorption and modulate the effects of inhibitors and inducers of CYP3A/CYP3A4 mediated metabolism. A growing number of animal data and clinical studies, both in vitro and in vivo, have indicated that concomitant administration of CYP3A/CYP3A4 inhibitors and/or P gp inhibitors can increase the oral bioavailability of a wide range of drugs, which are CYP3A/CYP3A4 and P glycoprotein substrates.