Date of Award
8-2010
Document Type
Thesis
Degree Name
Master of Science (MS)
Legacy Department
Biological Sciences
Committee Chair/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.
Recommended Citation
Green, Benjamin, "FOSINOPRIL, A POTENTIAL SUBSTRATE FOR MRP2, COMPETES WITH SEVERAL HIGH USE PHARMACEUTICALS FOR ELIMINATION" (2010). All Theses. 893.
https://open.clemson.edu/all_theses/893