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Research ArticleArticle

ROLE OF MRP2 IN THE HEPATIC DISPOSITION OF MYCOPHENOLIC ACID AND ITS GLUCURONIDE METABOLITES: EFFECT OF CYCLOSPORINE

Ian S. Westley, Leonie R. Brogan, Raymond G. Morris, Allan M. Evans and Benedetta C. Sallustio
Drug Metabolism and Disposition February 2006, 34 (2) 261-266; DOI: https://doi.org/10.1124/dmd.105.006122
Ian S. Westley
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Leonie R. Brogan
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Raymond G. Morris
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Allan M. Evans
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Benedetta C. Sallustio
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Abstract

Mycophenolic acid (MPA) is part of the immunosuppressant therapy for transplant recipients. This study examines the role of the canalicular transporter, Mrp2, and the effect of cyclosporin A (CsA), on the biliary secretion of the ether (MPAGe) and acyl (MPAGa) glucuronides of MPA. Isolated livers from Wistar rats (n = 6), or Wistar TR– rats (n = 6) were perfused with MPA (5 mg/l). A third group of Wistar rats (n = 6) was perfused with MPA and CsA (250 μg/l). There was no difference in the half-life, hepatic extraction ratio (EH), clearance or partial clearance of MPA to MPAGe, but there was a difference in partial clearance to MPAGa between control and CsA groups (0.9 ± 0.4 versus 0.5 ± 0.1 ml/min). TR– rats had a lower EH (0.59 ± 0.30 versus 0.95 ± 0.30), a lower clearance (18 ± 8 versus 29 ± 7 ml/min), and a longer half-life (19.5 ± 10.3 versus 10.1 ± 2.4 min) than controls. Compared to controls, MPAGe and MPAGa biliary excretion was reduced by 99% and 71.8%, respectively, in TR– rats, and 17.5% and 53.8%, respectively, in the MPA-CsA group. The biliary excretion of MPAGe is mediated by Mrp2, whereas that of MPAGa seems to depend on both Mrp2 and another unidentified canalicular transporter. Although CsA can inhibit Mrp2, our data suggest that it may also inhibit the hepatic glucuronidation of MPA in Wistar rats.

Footnotes

  • This work was funded, in part, by a grant-in-aid from the Australian Kidney Foundation.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.105.006122.

  • ABBREVIATIONS: MPA, mycophenolic acid; CsA, cyclosporin A; MPAGe, mycophenolate ether glucuronide; MPAGa, mycophenolate acyl glucuronide; HPLC, high performance liquid chromatography; IMPDH, inosine monophosphate dehydrogenase; AUC, area under the plasma concentration versus time curve; UGT, UDP-glucuronosyltransferase; CL, clearance.

    • Received June 19, 2005.
    • Accepted November 2, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (2)
Drug Metabolism and Disposition
Vol. 34, Issue 2
1 Feb 2006
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Research ArticleArticle

ROLE OF MRP2 IN THE HEPATIC DISPOSITION OF MYCOPHENOLIC ACID AND ITS GLUCURONIDE METABOLITES: EFFECT OF CYCLOSPORINE

Ian S. Westley, Leonie R. Brogan, Raymond G. Morris, Allan M. Evans and Benedetta C. Sallustio
Drug Metabolism and Disposition February 1, 2006, 34 (2) 261-266; DOI: https://doi.org/10.1124/dmd.105.006122

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Research ArticleArticle

ROLE OF MRP2 IN THE HEPATIC DISPOSITION OF MYCOPHENOLIC ACID AND ITS GLUCURONIDE METABOLITES: EFFECT OF CYCLOSPORINE

Ian S. Westley, Leonie R. Brogan, Raymond G. Morris, Allan M. Evans and Benedetta C. Sallustio
Drug Metabolism and Disposition February 1, 2006, 34 (2) 261-266; DOI: https://doi.org/10.1124/dmd.105.006122
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