Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: Implications for drug delivery and activity in cancer chemotherapy
✍ Scribed by Vincent J. Wacher; Chi-Yuan Wu; Leslie Z. Benet
- Publisher
- John Wiley and Sons
- Year
- 1995
- Tongue
- English
- Weight
- 642 KB
- Volume
- 13
- Category
- Article
- ISSN
- 0899-1987
No coin nor oath required. For personal study only.
✦ Synopsis
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, w h o 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.
CYP3A AND P-GP: COMPLEMENTARY ROLES IN MULTIDRUG RESISTANCE
CYP3A, like P-gp, is located primarily in hepatocytes and the biliary epithelial cells of the liver and the villous columnar epithelial cells of the jejunum [61. Significantly