Role of Mrp2 in the hepatic disposition of mycophenolic acid and its glucuronide metabolites: effect of cyclosporine.
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 microg/l). There was no difference in the half-life, hepatic extraction ratio (E(H)), 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 E(H) (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.
Westley
Ian S
IS
Department of Clinical Pharmacology, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville, South Australia, Australia 5011.
Brogan
Leonie R
LR
Morris
Raymond G
RG
Evans
Allan M
AM
Sallustio
Benedetta C
BC
D000818:Animals; D001659:Biliary Tract / Q000187:drug effects / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D004347:Drug Interactions; D020719:Glucuronides / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D009173:Mycophenolic Acid / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar
D016572:Cyclosporine; D020719:Glucuronides; D007166:Immunosuppressive Agents; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009173:Mycophenolic Acid