title: Effects of calcineurin inhibitors on pharmacokinetics of mycophenolic acid and its glucuronide metabolite during the maintenance period following renal transplantation.
abstract: Mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF) has been introduced into renal transplant immunosuppressant protocols in combination with calcineurin inhibitors (CNIs) and steroids. This study compared the pharmacokinetic profiles of MPA and its major metabolite MPA glucuronide (MPAG) in combination with tacrolimus (TAC) or cyclosporine (CyA) during the maintenance period (>6 months) following renal transplantation. There was no difference between TAC and CyA-treated groups in MPA plasma concentration before drug administration (C(0)). MPA C(0) in TAC and CyA-treated patients did not differ from that in patients who were not treated with a CNI. In patients treated with a CNI, MPAG C(0) was significantly greater in those treated with CyA compared with TAC. The MPAG/MPA ratio in CyA-treated patients was significantly greater than that in the TAC-treated group. We observed that C(0) of MPA was negatively correlated with that of TAC and CyA. Positive correlation between MPA C(0), MPAG C(0) and serum creatinine was stronger in patients treated with CyA compared with TAC. Our study suggests that CyA, but not TAC, inhibits enterohepatic circulation of MPAG as a secondary excretion pathway, and that renal function makes a major contribution to elimination of MPA and MPAG. We indicate that it may be necessary to estimate biliary excretion of MPAG to avoid the risk of intestinal injury in patients receiving combination therapy with TAC during the maintenance period.
authors.affiliation: Division of Hospital Pharmacy, Hamamatsu University School of Medicine, 1-20-1 Handa-yama, Hamamatsu 431-3192, Japan. naitou@hama-med.ac.jp
authors.forename: Takafumi
authors.initials: T
authors.lastname: Naito
authors.forename: Kazuko
authors.initials: K
authors.lastname: Shinno
authors.forename: Toshio
authors.initials: T
authors.lastname: Maeda
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kagawa
authors.forename: Hisakuni
authors.initials: H
authors.lastname: Hashimoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Otsuka
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Takayama
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ushiyama
authors.forename: Kazuo
authors.initials: K
authors.lastname: Suzuki
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Ozono
mesh_terms: D000293:Adolescent; D000328:Adult; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D005965:Glucuronates / Q000097:blood / Q000378:metabolism*; D020719:Glucuronides; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D011239:Prednisolone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D013997:Time Factors
chemical_list: D065095:Calcineurin Inhibitors; D005965:Glucuronates; D020719:Glucuronides; D007166:Immunosuppressive Agents; C113145:mycophenolic acid glucuronide; D016572:Cyclosporine; D011239:Prednisolone; D009173:Mycophenolic Acid; D016559:Tacrolimus