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Received for publication June 22, 2005.
Revised November 1, 2005.
Accepted for publication November 2, 2005.
Mycophenolic acid (MPA) is part of immunosuppressant therapy for transplant recipients. This study examines the role of the canalicular transporter Mrp2, and the effect of cyclosporin (CsA), on the biliary secretion of MPA's ether (MPAGe) and acyl (MPAGa) glucuronides. 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) were perfused with MPA and CsA (250 µg/L). There was no difference in MPA's half-life, hepatic extraction ratio (EH), clearance or partial clearance to MPAGe, but there was a difference in partial clearance to MPAGa between control and CsA groups (0.9±0.4 vs 0.5±0.1 mL/min). TR- rats had a lower EH (0.59±0.30 vs 0.95±0.30), clearance (18±8 vs 29±7 mL/min) and a longer half-life (19.8±10.6 vs 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 whilst that of MPAGa appears to depend on both Mrp2 and another unidentified canalicular transporter. Although CsA can inhibit Mrp2, our data suggest it may also inhibit the hepatic glucuronidation of MPA in Wistar rats.
Key words:
drug disposition, drug interactions, isolated perfused liver, transporters
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