Active secretion and enterocytic drug metabolism barriers to drug absorption

Intestinal phase I metabolism and active extrusion of absorbed drug have on ly recently been recognized as major determinants of oral drug bioavailabil ity. Both CYP3A4, the major phase I drug metabolizing enzyme in humans, and the multidrug efflux pump, P-glycoprotein (P-gp), are present at high leve ls in the villus enterocytes of the small intestine, the primary site of ab sorption for orally administered drugs. Moreover, these proteins are induce d by many of the same compounds and demonstrate a broad overlap in substrat e and inhibitor specificities, suggesting that they act as a concerted barr ier to drug absorption. Clinical studies have demonstrated that inhibition of CYP3A4-mediated intestinal metabolism can significantly improve the oral bioavailability of a wide range of drugs. Intestinal P-gp is a major route of elimination for both orally and intravenously administered anticancer d rugs in animal models, and experiements with the Caco-2 cell line have prov ided strong evidence that inhibition of intestinal P-gp is another means by which oral drug bioavailability could be enhanced. (C) 2001 Published by E lsevier Science B.V.