Mrp2 is involved in the efflux and disposition of fosinopril

Authors

  • Benjamin R. Green,

    1. Environmental Toxicology Graduate Program, Clemson University, Clemson, SC, 29634, USA
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    • University of Pittsburgh School of Medicine, Department of Surgery, Division of Cardiac Surgery, W917BSTWR, 200 Lothrop Street, Pittsburg, PA 15213, USA.
  • Lisa J. Bain

    Corresponding author
    1. Department of Biological Sciences, Clemson University, Clemson, SC, USA
    • Environmental Toxicology Graduate Program, Clemson University, Clemson, SC, 29634, USA
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Correspondence to: L. J. Bain, Environmental Toxicology Graduate Program, Clemson University, 132 Long Hall, Clemson, SC 29634, USA. E-mail: lbain@clemson.edu

ABSTRACT

The multidrug-resistance-associated proteins 1 and 2 (MRP1/MRP2) are transporters responsible for the efflux of drugs and endogenous compounds. Madin Darby canine kidney (MDCK) cells transfected with the human MRP1 or MRP2 genes were used to assess whether several widely used pharmaceuticals are potential substrates by examining their differential toxicity, accumulation and efflux. Loratadine, an antihistamine, was 1.4-fold less toxic to MRP1 cells and its retention was 1.3-fold lower than that from MDCK control cells. Fosinopril, an angiotensin converting enzyme inhibitor, was 2.4-fold less toxic and its retention was 4.5-fold lower in MRP2-transfected cells compared with control cells. To determine whether fosinopril contributed to a drug–drug interaction, fosinopril efflux was examined in vitro in combination with other known or suspected MRP2 substrates over a period of 20 min. When fosinopril was coincubated with desloratadine, loratadine or methotrexate, its retention was increased by 2-, 4.7- and 2-fold, respectively, which likely indicates that a drug–drug interaction is occurring. In vivo studies were conducted, in which FVB wild-type and FVB/Mrp2−/− mice were dosed with fosinopril and the known MRP2 substrate methotrexate, and tissues collected after 1 h. In mice lacking Mrp2, drug levels were reduced in the intestine by 1.5-fold, but increased in the liver, serum and kidneys, by 2.1-, 2.9- and 3-fold, respectively. These data suggest that, in the absence of Mrp2, fosinopril alters the retention of a second drug. These findings will help increase our understanding of the role that MRP2 plays in altering the retention and disposition of coadministered pharmaceuticals. Copyright © 2011 John Wiley & Sons, Ltd.

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