Protein binding study of mycophenolate mofetil, a new immunosuppressant, in human plasma and pharmacokinetics in renal transplant patients

Mycophenolate mofetil (MPM): a new immunosuppressant, is a morpholinoethyl ester of mycophenolic acid (MPA). The pharmacokinetics of MPA after multiple MPM administration to renal transplant patients and in vitro protein binding of MPA in human serum were studied. In in vitro binding study using human plasma, the unbound fraction of MPA was 2.5 +/- 0.7% (total MPA concentration was 100 mu g/ml). There was no change in the unbound fraction of MPA (about 1.5%) at a concentration range less than 300 mu M (96.1 mu g/ml) of total plasma MPA concentration. However, over 300 mu M, the unbound fraction of MPA increased depending on its total concentration. Scatchard plots for MPA binding to human serum albumin were biphasic, suggesting MPA has at least two specific binding sites on albumin molecule. The unbound fraction of MPA in human plasma was significantly increased by adding furosemide or lansoprazole. In renal transplant patients who received oral MPM medication at doses of 1000, 2000, 3000 and 1000 mg/day, the peak plasma concentrations of MPA were 4.4, 4.5, 10.6 and 15.1 mu g/ml, respectively. The mean peak times were 0.5 similar to 2h. The terminal elimination half-lives were 17.3 (1000mg/day), 13.2 (3000mg/day) and 15.2 (4000mg/day) h. The plasma concentration of the main metabolite of MPA, phenolic grucuronide, was ten times higher than plasma MPA concentration. The area under the plasma MPA concentration-time curve was correlated to the administerd dose. The plasma trough level of MPA did not reflect the administerd dose of MPM. MPM medication did not affect the pharmacokinetic parameters of cyclosporin A which concomitantly used for immunosuppressive therapy.