Monday, January 13, 2003: TOPIC IV: HORMONAL INFLUENCE ON TREATMENT AND THE EFFECT OF TREATMENTS ON CONTRACEPTIVE METHODS
Basic Pharmacological Interactions and How They May Impact on One Another
Our laboratory has been very interested in the interactive nature of the multidrug resistance transporter MDR1 and the major human cytochrome P450 drug-metabolizing enzyme, CYP3A4. We have recently shown in a model cellular system that inhibiting the MDR1 transporter can change the metabolism of CYP3A4 substrates, even when the enzyme has not been modified. We have demonstrated that this cellular system in one direction is a model for what occurs in the human intestine, and that transport in the reverse direction is a model for what happens in the human liver. We had previously noted a marked difference in the pharmacokinetics of CYP3A4 substrates studied in our laboratory in women versus men, where clearance of the drugs studied was greater in women. We recently hypothesized1 that this difference in metabolism of CYP3A4 substrates only occurs for compounds that are also substrates for MDR1, and that the observed differences in metabolism resulted from differences in MDR1 liver concentrations between men and women. More recently, we have investigated the effects of the menstrual cycle on endometrial and intestinal MDR1, and their potential effects on the pharmacokinetics of the HIV protease inhibitor nelfinavir. Our preliminary results in African-American and Caucasian HIV-infected and HIV-negative women show that endometrial MDR1 increases during the mid-luteal phase versus the follicular phase, and that changes in nelfinavir systemic pharmacokinetics are correlated with intestinal MDR1 levels. We studied both African-American and Caucasian women because of the marked difference in allelic variants for MDR1 in these two populations. We continue to investigate the pharmacogenetic implications of MDR1 activity in treating HIV-infected women, in addition to the interactive nature of the enzyme and the transporter.
This study was partly supported by National Institutes of Health (NIH) grant HD40543.
© 2005 Lippincott Williams & Wilkins, Inc.
1. Cummins CL, Wu CY, Benet LZ. Sex-related differences in the clearance of cytochrome P450 3A4 substrates may be caused by P-glycoprotein. Clin Pharmacol Ther 2002; 72:474–489.