Date of Award

8-2010

Document Type

Thesis

Degree Name

Master of Science (MS)

Legacy Department

Biological Sciences

Advisor

Bain, Lisa J

Committee Member

van den Hurk , Peter

Committee Member

Tzeng , Tzuen Rong J

Abstract

The multidrug-resistance associated protein 2 (MRP2) is a membrane-bound transporter responsible for the efflux of a variety of drugs and endogenous compounds. MDCK cells transfected with the human MRP2 gene were used to assess whether several highly used pharmaceuticals were potential substrates by examining their differential toxicity, accumulation, and efflux. Fosinopril, an ACE inhibitor, was 2.4-fold less toxic to the MRP2 transfected cells compared to mock transfected cells, suggesting that fosinopril is a potential MRP2 substrate. In addition, fosinopril was effluxed more rapidly, as the MRP2 cells only retained 13 % of the dosed fosinopril after 20 minutes compared with 60 % retained in the control cells. To determine whether fosinopril might contribute to a drug-drug interaction, fosinopril efflux was examined in combination with several other known or suspected MRP2 substrates. When fosinopril was coincubated with desloratadine, its retention was increased by 2-fold, with loratadine, its retention was increased by 4.7-fold, and with methotrexate, its retention was increased by 2-fold. The increases in retention with multiple drugs likely indicate that a drug-drug interaction is occurring. To further clarify whether fosinopril was a substrate for Mrp2, we dosed wild-type and Mrp2 knockout mice with the known Mrp2 substrate methotrexate and fosinopril. In mice lacking Mrp2, fosinopril and methotrexate levels were increased in the serum and the kidneys, which suggest that the lack of Mrp2 favors fosinopril excretion through the urine rather than the feces. Assessing the transport of highly prescribed pharmaceuticals by MRP transporters is important to determine the potential for drug-drug interactions, and will aid clinicians in minimizing drug toxicity.

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