A great challenge to the continuing search for more efficient and specific anticancer drugs is the unified response by tumor cells to rid themselves of these agents, a process loosely labeled multidrug resistance. While multidrug resistance has now become synonymous with the P-glycoprotein (P-gp) drug-efflux pump, in reality this process encompasses the full range of cellular responses to xenobiotics, including upregulation of drug-metabolism processes [I, 2]. Research in our laboratory has focused on cytochrome P450 (CYP) 3A, the enzyme responsible for phase I metabolism of over 50% of drugs administered to humans (National Academy of Sciences, Institute of Medicine workshop:" Enzymes of Drug Metabolism: Importance to Drug Safety and Efficacy," January 25 and 26, 1993) and particularly the contribution of intestinal CYP3A-mediated metabolism to the bioavailability of orally administered drugs such as cyclosporine. The importance of intestinal CYP3A in decreasing oral-drug bioavailability is even now not recognized by many drug-delivery scientists, who have previously been concerned exclusively with the physicochemical aspects of drug absorption. Similarly, such scientists are just beginning to appreciate that P-gp is expressed at high levels on the apical surfaces of columnar epithelial cells in the jejunum [3] and is also expected to play a part in the absorption of many drugs. Previous reports have noted that various inhibitors of P-gp activity in tumor cells are also CYP3A substrates [4, 51, and the more detailed investigation described here revealed a number of striking overlaps between CYP3A and P-gp that suggest that these enzymes have complementary roles in the pharrnacokinetics of drug absorption and elimination that are particularly relevant to cancer chemotherapy.