The impact of P-glycoprotein and Mrp2 on mycophenolic acid levels in mice.
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.
Wang
Jian
J
Department of Biomedical Engineering, University of Southern California, 1042 Downey Way, Los Angeles, CA 90089, United States.
Figurski
Michael
M
Shaw
Leslie M
LM
Burckart
Gilbert J
GJ
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*
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