title: Cyclosporine interacts with mycophenolic acid by inhibiting the multidrug resistance-associated protein 2.
abstract: In mycophenolate mofetil (MMF)-treated organ transplant recipients, lower mycophenolic acid (MPA) plasma concentrations have been found in cyclosporine (CsA) compared with tacrolimus (Tac)-based immunosuppressive regimens. We previously demonstrated that CsA decreases exposure to MPA and increases exposure to its metabolite MPA-glucuronide (MPAG), possibly by interfering with the biliary excretion of MPAG. To elucidate the role of the multidrug resistance-associated protein (Mrp)-2 in the interaction between MMF and CsA, we treated three groups of 10 Mrp2-deficient rats (TR- rat) for 6 days with either vehicle, CsA (8 mg/kg) or Tac (4 mg/kg) by oral gavage. Hereafter, co-administration with MMF (20 mg/kg) was started in all groups and continued through day 14. The 24-h MPA/MPAG area under the concentration-time curve (AUC) was determined after single (day 7) and multiple MMF doses (day 14). On both study days, there were no significant differences in the mean MPA and MPAG AUC between CsA and Tac-treated animals. We conclude that the pharmacokinetics of MMF are comparable in Mrp2-deficient rats receiving either CsA or Tac as co-medication. This finding suggests that CsA-mediated inhibition of the biliary excretion of MPAG by the Mrp2 transporter is the mechanism responsible for the interaction between CsA and MMF.
authors.affiliation: Department of Internal Medicine, Renal Transplant Unit, Erasmus University Medical Center, Rotterdam, The Netherlands. d.a.hesselink@erasmusmc.nl
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Hesselink
authors.forename: Reinier M
authors.initials: RM
authors.lastname: van Hest
authors.forename: Ron A A
authors.initials: RA
authors.lastname: Mathot
authors.forename: Fred
authors.initials: F
authors.lastname: Bonthuis
authors.forename: Willem
authors.initials: W
authors.lastname: Weimar
authors.forename: Ron W F
authors.initials: RW
authors.lastname: de Bruin
authors.forename: Teun
authors.initials: T
authors.lastname: van Gelder
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001663:Bilirubin / Q000097:blood; D016572:Cyclosporine / Q000493:pharmacokinetics*; D004357:Drug Synergism; D004492:Edetic Acid / Q000494:pharmacology; D020719:Glucuronides / Q000737:chemistry; D006084:Graft Rejection; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors*; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology; D016377:Organ Transplantation; D010919:Placebos; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000494:pharmacology; D013997:Time Factors
chemical_list: D001663:Bilirubin; D016572:Cyclosporine; D004492:Edetic Acid; D020719:Glucuronides; D007166:Immunosuppressive Agents; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009173:Mycophenolic Acid; D010919:Placebos; D016559:Tacrolimus