mycophenolic-acid-glucuronide and Diabetes-Mellitus

Mycophenolate mofetil [MMF, the prodrug of mycophenolic acid (MPA)] is usually administered at double doses with cyclosporine than with tacrolimus because it is believed that MPA exposure is lower during cyclosporine therapy. This study aimed to compare 12 hour, steady-state concentration-time profiles of MPA and its phenol- and acyl-glucuronide metabolites (MPAG and AcMPAG, respectively) in stable kidney transplant recipients maintained either on cyclosporine (n = 12) or tacrolimus (n = 12). During the absorption phase in the cyclosporine group, dose-normalized concentrations of total and free MPA were significantly higher but the overall area under the concentration-time curve (AUC0-12) was not significantly different. Additionally, exposure to AcMPAG was higher in the cyclosporine group (P < 0.05). Ten of 12 patients in the cyclosporine group were on ketoconazole therapy; however, the exposure to MPA or MPAG was not different when MMF was given orally to Sprague-Dawley rats with or without ketoconazole. In conclusion, cyclosporine modulates the disposition of MPA and metabolites differently from tacrolimus; however, patients on cyclosporine may not require double doses of MMF to achieve the same exposure.

Topics: Administration, Oral; Aged; Animals; Antibiotics, Antineoplastic; Area Under Curve; Cyclosporine; Diabetes Mellitus; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Glucuronides; Humans; Immunosuppressive Agents; Ketoconazole; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Rats; Rats, Sprague-Dawley; Tacrolimus