2000 WHRG Grant Program

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Quantification of Hepatic CYP3A Activity in Women with ESRD

Thomas C. Dowling, Pharm.D., Ph.D.
School of Pharmacy, University of Maryland, Baltimore

Cytochrome P450 3A (CYP3A) is the most prominent CYP isozyme expressed in the human liver, comprising approximately 30% of total CYP, and is considered the most important drug metabolizing enzyme in the body. Recent studies on gender-differences in drug metabolism are conflicting, and it is unknown whether such differences exist in women with kidney disease. Kidney disease is a common disorder; in 1997 the prevalence of end-stage renal disease (ESRD) in the U.S. was 300,000, of which 54% of these were women. Experimental evidence suggests that alterations in liver function and biotranformation of drugs can occur in renal failure, possibly due to accumulation of endogenous toxins that are normally eliminated by the kidney. It is entirely unclear whether these renal toxins have detrimental effects on CYP3A-mediated drug metabolism. Lack of such knowledge is an important problem since women with ESRD may be at increased risk of drug toxicity due to reduced CYP3A-mediated metabolism and drug interactions.

The central hypothesis that drives this application is that women with ESRD have reduced CYP3A-mediated drug metabolism as compared to healthy men and women. The rationale for the proposed research is that, once it is known whether CYP3A activity is reduced in women with ESRD, new drug dosing strategies for selected CYP3A drugs may be proposed. The specific aims of this project are as follows: 1) to characterize baseline hepatic CYP3A activity in women receiving chronic hemodialysis, and 2) to determine the effect of ESRD on hepatic CYP3A induction. A clinical study will be conducted in women receiving chronic hemodialysis to characterize CYP3A activity at baseline and after rifampin induction. Quantification of hepatic CYP3A activity will be accomplished using the erythromycin breath test (EBT) and subjects will undergo measurement of endogenous carbon dioxide production to validate previous assumptions of this test. These results will be significant, because they are expected to further our understanding of gender-effects on hepatic CYP3A activity. This is also important since this patient population is at increased risk of drug toxicity and drug interations due to the numerous medications that are either metabolized by CYP3A or alter the activity of this important metabolic pathway.