Pharmacology: Pharmacodynamics: Mechanism of Action: Mycophenolate mofetil is the 2-morpholinoethyl ester of mycophenolic acid (MPA). MPA is a potent, selective, uncompetitive, and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), which inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. T- and B-lymphocytes are critically dependent for their proliferation on de novo synthesis of purines, whereas other cell types can utilize salvage pathways. Therefore, MPA has potent cytostatic effects on lymphocytes than on other cells.
Pharmacokinetics: Absorption: Following oral administration, mycophenolate mofetil undergoes rapid and extensive absorption and complete presystemic metabolism to the active metabolite, MPA. The mean bioavailability of oral mycophenolate mofetil, based on MPA AUC, is 94% relative to IV.
Food had no effect on the extent of absorption (MPA AUC) of mycophenolate mofetil when administered at doses of 1.5 g BID to renal transplant patients. However, MPA Cmax was decreased by 40% in the presence of food.
In the early post-transplant period (<40 days post-transplant), renal, cardiac and hepatic patients have mean MPA AUCs and Cmax lower compared to the late post-transplant period (3-6 months post-transplant).
Distribution: At clinically relevant concentrations, MPA is 97% bound to plasma albumin. Following oral administration of mycophenolate mofetil, the mean volume of distribution of MPA is 4 l/kg.
Metabolism: Following oral administration, mycophenolate mofetil undergoes complete presystemic metabolism to the active metabolite, MPA. MPA is metabolized principally by glucuronyl transferase to form the phenolic glucuronide of MPA (MPAG) which is inactive metabolite.
As a result of enterohepatic recirculation, secondary increases in the plasma MPA concentration are usually observed at approximately 6 - 12 hours post-dose. A reduction in the AUC of MPA of approximately a 40% is associated with the co-administration of cholestyramine (4 g TID), indicating that there is a significant amount of enterohepatic recirculation.
Excretion: A negligible amount of substance is excreted as MPA (<1% of dose) in the urine. Orally administered radiolabeled mycophenolate mofetil results in complete recovery of the administered dose, with 93% of the administered dose recovered in the urine and 6% recovered in feces. Most (about 87%) of the administered dose is excreted in the urine as MPAG.
At clinically encountered concentrations, MPA and MPAG are usually not removed by hemodialysis. However, at high MPAG plasma concentrations (>100 μg/mL), small amounts of MPAG are removed. Half-life of elimination for oral is 18 hours whereas median time to peak plasma concentration is 1-1.5 hours.