Pharmacokinetics of mycophenolate mofetil in patients with end-stage renalfailure

Background. Mycophenolate mofetil (MMF) acts as a prodrug for the immunosup pressive drug mycophenolic acid (MPA). It is rapidly converted to MPA follo wing oral ingestion. MPA is metabolized to MPA glucuronide (MPAG). which is renally excreted. This study examines the pharmacokinetics of MPA and MPAG in patients with end-stage renal failure who were on hemodialysis (N = 10) or peritoneal dialysis (N = 10) treatment. Methods. After an overnight fast, a single oral dose of 1 g MMF was given. Plasma concentrations of MPA and MPAG were measured from 0 (predose) to 36 hours after administration, using high-performance liquid chromatography (H PLC). The area under the concentration time curve (AUC) from 0 to 36 hours was calculated using the trapezoidal rule. Results. Mean (+/- SD) AUC for MPA was 55.7 +/- 32.6 mg/L . h for hemodialy sis patients and 44.7 +/- 14.7 mg/L . h for peritoneal dialysis patients, w hich is similar to expected values for subjects with normal renal function. The mean (+/- SD) maximum plasma concentration (C-max) for MPA was lower t han would he expected for subjects with normal renal function (16.01 +/- 10 .61 mg/L for hemodialysis, 11.48 +/- 4.98 mg/L for peritoneal dialysis). MP AG clearance was prolonged with AUC approximately five times what would be expected in subjects with normal renal function (1565 +/- 596 mg/L . h for hemodialysis, 1386 +/- 410 mg/L . h for peritoneal dialysis). There was no significant difference for any of the pharmacokinetic parameters between su bjects on hemodialysis and those on peritoneal dialysis. Plasma concentrati ons of MPA and MPAG did not fall significantly during hemodialysis. No MPA was detectable in hemodialysis or peritoneal dialysis fluid, but small amou nts of MPAG were detected in hemodialysis fluid in 1 out of 10 subjects and in peritoneal dialysis fluid in 3 out of 10 subjects. Conclusions. The accumulation of MPAG may be responsible for the poor gastr ointestinal tolerance of this drug in dialysis patients and probably limits the maximum dose of MMF that can be tolerated.