title: The impact of P-glycoprotein and Mrp2 on mycophenolic acid levels in mice.
abstract: Considerable variability has been observed in the exposure to mycophenolic acid (MPA) in transplant patients. The objective of this study was to clarify the roles of two important transporters, P-gp and Mrp2, in MPA absorption using an in vivo model. FVB strain wild-type, Mdr1a/1b(-/-) and Mrp2(-/-) mice were subjected to the administration of mycophenolate mofetil (MMF) alone or MMF in combination with cyclosporine (CsA), an immunosuppressive inhibitor of P-gp and Mrp2. At 30 min following treatment, the MPA levels in Mdr1a/1b(-/-) and Mrp2(-/-) mice were markedly increased as compared to wild-type mice. In contrast to the reduced MPA concentrations observed at 60 and 120 min in the CsA-treated groups, CsA produced increased mycophenolate glucuronide (MPAG) plasma levels in CsA-treated mice at each sampling time. Brain concentrations of MPA were elevated in the Mdr1a/1b(-/-) mice at 30 min after MMF in conjunction with increased plasma MPA concentrations, but not in the wild-type or the Mrp2(-/-) mice. This study demonstrated that: a) MPA appears to be a substrate for P-gp, and b) MPA plasma concentrations are influenced by multiple membrane transporters. Drug-transporter interactions must be considered in patients receiving mycophenolic acid products.
authors.affiliation: Department of Biomedical Engineering, University of Southern California, 1042 Downey Way, Los Angeles, CA 90089, United States.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Michael
authors.initials: M
authors.lastname: Figurski
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Shaw
authors.forename: Gilbert J
authors.initials: GJ
authors.lastname: Burckart
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000008:administration & dosage; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D020719:Glucuronides / Q000097:blood*; D006084:Graft Rejection / Q000188:drug therapy; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D051379:Mice; D018345:Mice, Knockout; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016572:Cyclosporine; D004338:Drug Combinations; D020719:Glucuronides; D007166:Immunosuppressive Agents; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009173:Mycophenolic Acid; C113145:mycophenolic acid glucuronide