RT Journal Article SR Electronic T1 ROLE OF MRP2 IN THE HEPATIC DISPOSITION OF MYCOPHENOLIC ACID AND ITS GLUCURONIDE METABOLITES: EFFECT OF CYCLOSPORINE JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 261 OP 266 DO 10.1124/dmd.105.006122 VO 34 IS 2 A1 Ian S. Westley A1 Leonie R. Brogan A1 Raymond G. Morris A1 Allan M. Evans A1 Benedetta C. Sallustio YR 2006 UL http://dmd.aspetjournals.org/content/34/2/261.abstract AB 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. The American Society for Pharmacology and Experimental Therapeutics