The pharmacokinetics of the immunosuppressant mycophenolate mofetil have been investigated in healthy volunteers and mainly in recipients of renal allografts. Following oral administration, mycophenolate mofetil was rapidly and completely absorbed, and underwent extensive presystemic de-esterification. Systemic plasma clearance of intravenous mycophenolate mofetil was around 10 L/min in healthy individuals, and plasma mycophenolate mofetil concentrations fell below the quantitation limit (0.4 mg/L) within 10 minutes of the cessation of infusion. Similar plasma mycophenolate mofetil concentrations were seen after intravenous administration in patients with severe renal or hepatic impairment, implying that the de-esterification process had not been substantially affected. Mycophenolic acid, the active immunosuppressant species, is glucuronidated to a stable phenolic glucuronide (MPAG) which is not pharmacologically active. Over 90% of the administered dose is eventually excreted in the urine, mostly as MPAG. The magnitude of the MPAG renal clearance indicates that active tubular secretion of MPAG must occur. At clinically relevant concentrations, mycophenolic acid and MPAG are about 97% and 82% bound to albumin, respectively. MPAG at high (but clinically realisable) concentrations reduced the plasma binding of mycophenolic acid. The mean maximum plasma mycophenolic acid concentration (Cmax) after a mycophenolate mofetil 1 g dose in healthy individuals was around 25 mg/L, occurred at 0.8 hours postdose, decayed with a mean apparent half-life (t1/2) of around 16 hours, and generated a mean total area under the plasma concentration-time curve (AUC infinity) of around 64 mg.h/L. Intra- and interindividual coefficients of variation for the AUC infinity of the drug were estimated to be 25% and 10%, respectively. Intravenous and oral administration of mycophenolate mofetil showed statistically equivalent MPA AUC infinity values in healthy individuals. Compared with mycophenolic acid, MPAG showed a roughly similar Cmax about 1 hour after mycophenolic acid Cmax, with a similar t1/2 and an AUC infinity about 5-fold larger than that for mycophenolic acid. Secondary mycophenolic acid peaks represent a significant enterohepatic cycling process. Since MPAG was the sole material excreted in bile, entrohepatic cycling must involve colonic bacterial deconjugation of MPAG. An oral cholestyramine interaction study showed that the mean contribution of entrohepatic cycling to the AUC infinity of mycophenolic acid was around 40% with a range of 10 to 60%. The pharmacokinetics of patients with renal transplants (after 3 months or more) compared with those of healthy individuals were similar after oral mycophenolate mofetil. Immediately post-transplant, the mean Cmax and AUC infinity of mycophenolic acid were 30 to 50% of those in the 3-month post-transplant patients. These parameters rose slowly over the 3-month interval. Slow metabolic changes, rather than poor absorption, seem responsible for this nonstationarity, since intravenous and oral administration of mycophenolate mofetil in the immediate post-transplant period generated comparable MPA AUC infinity values. Renal impairment had no major effect on the pharmacokinetic of mycophenolic acid after single doses of mycophenolate mofetil, but there was a progressive decrease in MPAG clearance as glomerular filtration rate (GFR) declined. Compared to individuals with a normal GFR, patients with severe renal impairment (GFR 1.5 L/h/1.73m2) showed 3-to 6-fold higher MPAG AUC values. In rental transplant recipients during acute renal impairment in the early post-transplant period, the plasma MPA concentrations were comparable to those in patients without renal failure, whereas plasma MPAG concentrations were 2- to 3-fold higher. Haemodialysis had no major effect on plasma mycophenolic acid or MPAG. Dosage adjustments appear to not be necessary either in renal impairment or during dialysis. (ABSTRACT TRUN