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From Bench to Bedside: Utilization of an In Vitro Model to Predict Potential Drug-Drug Interactions in the Kidney: The Digoxin-Mifepristone Example

From the Division of Clinical Pharmacology and Toxicology, The Research Institute, The Hospital for Sick Children, and Departments of Pediatrics and Pharmacology, University of Toronto.

Drug interactions are a common source of drug-induced toxicity. For drugs with narrow therapeutic windows, such as digoxin, an understanding of the potential mechanisms by which drugs might interact is essential to clinical practice. This article describes the utility of a renal tubular cell culture model in the prediction of drug interactions involving P-glycoprotein. Digoxin is a cardiac glycoside that undergoes active secretion in the renal tubules by the MDR1 (P-glycoprotein) drug efflux pump. Mifepristone (RU486) is a recently introduced abortifacient that is largely unstudied in terms of drug-drug interactions. The authors used an in vitro model to study the effects of mifepristone on the renal tubular secretion and cellular uptake of digoxin by Madin-Darby canine kidney (MDCK) cells. Mifepristone significantly inhibited the renal tubular secretion of digoxin (p = 0.0005), without interfering with its ability to enter the renal tubular cell. Similar results were found with the P-glycoprotein substrate vinblastine. The findings suggest that drug interactions may result if mifepristone is administered with P-glycoprotein substrates, highlighting the usefulness of this model in the study of not only common but also rare combinations of drugs.

Key Words: Mifepristone • RU486 • P-glycoprotein • digoxin • vinblastine • drug interaction • cell culture • MDCK cells

Address for reprints: Dr. Cindy Woodland, Department of Pharmacology, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.

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