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Pharmacokinetics and Bioavailability of Mycophenolate Mofetil in Healthy Subjects after Single‐Dose Oral and Intravenous Administration
Author(s) -
Bullingham Roy,
Monroe Scot,
Nicholls Andrew,
Hale Michael
Publication year - 1996
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/j.1552-4604.1996.tb04207.x
Subject(s) - pharmacokinetics , mycophenolic acid , bioavailability , mycophenolate , oral administration , pharmacology , prodrug , medicine , enterohepatic circulation , glucuronide , crossover study , urine , area under the curve , transplantation , metabolism , alternative medicine , pathology , placebo
A randomized, crossover study of 12 healthy volunteers was conducted with single, 1.5‐g doses of mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), after oral and intravenous administration. During the intravenous infusion, phase systemic plasma clearance of MMF was ∼10 L/min and the half‐life (t 1/2 ) was a few minutes. After oral administration, however, plasma MMF was below quantitation limits at all times. The plasma MPA profile of oral MMF showed a sharp peak at ∼1 hour and a secondary peak at 8 to 12 hours. Mean apparent plasma t 1/2 of MPA was similar for both routes (∼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 rule), with mean bioavailability of MPA from oral administration of MMF estimated as 94.1% relative to the intravenous route. Total plasma AUC of mycophenolic acid glucuronide (MPAG), the sole metabolite of MPA, was four‐ to five‐fold higher than MPA. Total 48‐hour MPAG recovery in urine was statistically equivalent for the two routes and represented a mean of 70% of administered drug; corresponding MPA recovery was less than 1%. Renal clearance (CI r ) values required transport mechanisms for MPAG, but not for MPA. The CI R of MPAG was statistically higher after intravenous administration than oral administration. MMF administered orally undergoes rapid, complete absorption and essentially complete 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.