Effects of Calcineurin Inhibitors on Pharmacokinetics of Mycophenolic Acid and Its Glucuronide Metabolite during the Maintenance Period Following Renal Transplantation

• Published in: Biological & Pharmaceutical Bulletin 2006, Vol.29(2), pp.275-280
• Main Authors: Naito, Takafumi, Shinno, Kazuko, Maeda, Toshio, Kagawa, Yoshiyuki, Hashimoto, Hisakuni, Otsuka, Atsushi, Takayama, Tatsuya, Ushiyama, Tomomi, Suzuki, Kazuo, Ozono, Seiichiro
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; calcineurin inhibitor; Calcineurin Inhibitors; Cyclosporine - administration & dosage; Cyclosporine - blood; Cyclosporine - pharmacokinetics; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Female; Glucuronates - blood; Glucuronates - metabolism; Glucuronides; Graft Rejection - prevention & control; Humans; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - blood; Immunosuppressive Agents - pharmacokinetics; individual variability; Kidney Transplantation; maintenance period; Male; Metabolic Clearance Rate; Middle Aged; mycophenolic acid; Mycophenolic Acid - administration & dosage; Mycophenolic Acid - analogs & derivatives; Mycophenolic Acid - blood; Mycophenolic Acid - metabolism; Mycophenolic Acid - pharmacokinetics; Prednisolone - administration & dosage; Prednisolone - blood; Prednisolone - pharmacokinetics; renal transplantation; Tacrolimus - administration & dosage; Tacrolimus - blood; Tacrolimus - pharmacokinetics; therapeutic drug monitoring; Time Factors
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.29.275

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 (C0). MPA C0 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 C0 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 C0 of MPA was negatively correlated with that of TAC and CyA. Positive correlation between MPA C0, MPAG C0 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.