PHARMACOKINETICS AND BIOAVAILABILITY OF MYCOPHENOLATE MOFETIL IN HEALTHY-SUBJECTS AFTER SINGLE-DOSE ORAL AND INTRAVENOUS ADMINISTRATION

A randomized, crossover study of 12 healthy volunteers was conducted w ith single, 1.5-g doses of mycophenolate mofetil (MMF), a prodrug of m ycophenolic acid (MPA), after oral and intravenous administration. Dur ing the intravenous infusion, phase systemic plasma clearance of MMF w as similar to 10 L/min and the half-life (t(1/2)) was a few minutes. A fter oral administration, however, plasma MMF was below quantitation l imits at all times. The plasma MPA profile of oral MMF showed a sharp peak at similar to 1 hour and a secondary peak at 8 to 12 hours. Mean apparent plasma t(1/2) of MPA was similar for both routes (similar to 17 hours). The area under the concentration-time curve (AUC)-from time 0 to 24 hours was statistically higher for intravenous than for oral administration, but total AUC showed statistical equivalence (80-120 r ule), with mean bioavailability of MPA from oral administration of MMF estimated as 94.1% relative to the intravenous route. Total plasma AU C of mycophenolic acid glucuronide (MPAG), the sole metabolite of MPA, was four- to five-fold higher than MPA. Total 48-hour MPAG recovery i n urine was statistically equivalent for the two routes and represente d a mean of 70% of administered drug; corresponding MPA recovery was l ess than 1%. Renal clearance (Cl-R) values required transport mechanis ms for MPAG, but not for MPA. The Cl-R of MPAG was statistically highe r after intravenous administration than oral administration. MMF admin istered orally undergoes rapid, complete absorption and essentially co mplete presystemic deesterification. There was presystemic removal of MPA, but enterohepatic circulation compensated for the first pass loss . Renal metabolism of MPA also may have occurred.