The gut as a barrier to drug absorption - Combined role of cytochrome P4503A and P-glycoprotein

Intestinal phase I metabolism and active extrusion of absorbed drug have re cently been recognised as major determinants of oral bioavailability. Cytoc hrome P450 (CYP) 3A, the major phase I drug metabolising enzyme in humans, and the multidrug efflux pump, P-glycoprotein, are present at high levels i n the villus tip of enterocytes in the gastrointestinal tract, the primary site of absorption for orally administered drugs. The importance of CYP3A a nd P-glycoprotein in limiting oral drug delivery is suggested to us by thei r joint presence in small intestinal enterocytes, by the significant overla p in their substrate specificities, and by the poor oral bioavailability of joint substrates for these 2 proteins. These proteins are induced or inhib ited by many of the same compounds. A growing number of preclinical and clinical studies have demonstrated that the oral bioavailability of many CYP3A and/or P-glycoprotein substrate dru gs can be increased by concomitant administration of CYPSA inhibitors and/o r P-glycoprotein inhibitors. We believe that further understanding the phys iology and biochemistry of the interactive nature of intestinal CYP3A and P -glycoprotein will be important in defining, controlling, and improving ora l bioavailability of CYP3A/P-glycoprotein substrates.