title: [Optimal immunosuppressive therapy based on pharmacokinetics and pharmacodynamics of antimetabolites in clinical practice].
abstract: An immunosuppressive antimetabolite, mycophenolate mofetil (MMF), has been widely used in combination with a calcineurin inhibitor for organ transplantation and autoimmune diseases. A fixed dosing of MMF often causes bone marrow toxicity or cytomegalovirus antigenemia under the optimal dosing of calcineurin inhibitors. Pharmacokinetic characteristics of MMF and its relation to the degree of immune suppression have not been fully clarified in clinical practice. This review summarizes our achievements on pharmacokinetic disposition of mycophenolic acid (MPA) and inosine 5'-monophosphate dehydrogenase (IMPDH) activity in patients with kidney transplantation and with lupus nephritis. Contribution of enterohepatic recirculation to plasma disposition of MPA in lupus nephritis patients was similar to that in tacrolimus-treated kidney transplant recipients. MPA pharmacokinetics in lupus nephritis was characterized by high MPA clearance most likely due to better renal function. In addition, concomitant metal cation decreased MPA concentration in patients receiving tacrolimus but not cyclosporine. This interaction may depend on amount of biliary-excreted MPA glucuronide. Renal clearance of MPA was higher in cyclosporine- than tacrolimus-treated patients. Its ratio to creatinine clearance was much higher than unbound fraction of MPA in each calcineurin inhibitor treatment. These kinetic data revealed the presence of renal tubular secretion in the urinary excretion process. In multivariate analysis, the plasma disposition of MPA and its glucuronides affected IMPDH activity in erythrocytes. The IMPDH activity might be a useful marker reflecting a long-term exposure by MPA. Our findings in this review would contribute to optimal dosing of MMF in immunosuppressive regimen including a calcineurin inhibitor.
authors.affiliation: Department of Hospital Pharmacy, Hamamatsu University School of Medicine, Shizuoka, Japan. naitou@hama-med.ac.jp
authors.forename: Takafumi
authors.initials: T
authors.lastname: Naito
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D065095:Calcineurin Inhibitors; D016572:Cyclosporine; D004334:Drug Administration Schedule; D004347:Drug Interactions; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D020719:Glucuronides; D006801:Humans; D007168:IMP Dehydrogenase / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008181:Lupus Nephritis; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D016559:Tacrolimus
chemical_list: D000963:Antimetabolites; D065095:Calcineurin Inhibitors; D020719:Glucuronides; D007166:Immunosuppressive Agents; C113145:mycophenolic acid glucuronide; D016572:Cyclosporine; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid; D016559:Tacrolimus