CYP3A4 present in small bowel enterocytes can catalyze substantial metabolism of some orally administered drugs and, thus, exerts a first-pass effect. Recent data indicate that the P-glycoprotein (the MDR 1 gene product) in the enterocyte brush border also limits the bioavailability of many of the same drugs that interact with CYP3A. It has been proposed that P-glycoprotein and CYP3A4 may be functionally linked because (a) the two proteins are co-localized within the digestive tract and within enterocytes, (b) they share many of the same substrates and (c) they are co-inducible in response to at least some xenobiotics. There are several potential mechanisms whereby the functions of P-glycoprotein and CYP3A4 could be complimentary. First, Pgp may limit absorption in the proximal small bowel, shifting it to more distal, less catalytically efficient segments that contain lower amounts of CYP3A4. Second, Pgp may function to prolong the duration of absorption. This might increase the duration of exposure of drug to and, hence, the extent of metabolism by enterocyte CYP3A4. Finally, Pgp may preferentially remove from the enterocyte primary drug metabolites that are themselves substrates for CYP3A4. This would limit product inhibition and facilitate primary metabolism catalyzed by CYP3A4. Characterization of the roles of CYP3A4 and Pgp in limiting oral drug availability may be aided by recent success in the development of human intestinal cell lines that stably express both CYP3A4 and Pgp.