Pharmacology: Mechanism of Action: Mycophenolate mofetil is the 2-morpholinoethyl ester of mycophenolic acid (MPA). It is a potent, selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase, and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. Because T- and B-lymphocytes are critically dependent for their proliferation on the de novo synthesis of purines whereas other cell types can utilise salvage pathways, MPA has more potent cytostatics effects on lymphocytes than on other cells.
Pharmacokinetics: Following oral administration, mycophenolate mofetil undergoes rapid and extensive and complete presystemic metabolism to the active metabolite, MPA. As evidenced by suppression acute rejection following renal transplantation, the immunosuppressant activity of mycophenolate is correlated with MPA concentration. The mean bioavailability of oral mycophenolate mofetil, based on MPA AUC, is 94% relative to mycophenolate mofetil. Food had no effect on the extent of absorption (MPA AUC) of mycophenolate mofetil when administered at doses of 1.5 g twice-daily to renal transplant patients. However, MPA Cmax was decreased by 40% in the presence of food. Mycophenolate mofetil is not measurable systemically in plasma following oral administration. MPA at clinically relevant concentrations, is 97% bound to plasma albumin.
As a result of enterohepatic recirculation, secondary increases in plasma MPA concentration are usually observed at approximately 6-12 hrs post-dose. A reduction in the AUC of MPA of approximately 40% is associated with the co-administration of cholestyramine (4 g three times daily), indicating that there is a significant amount of enterohepatic recirculation.
MPA is metabolized principally by glucuronyl transferase to form the phenolic glucuronide of MPA (MPAG), which is not pharmacologically active.
A negligible amount of substance is excreted as MPA (<1% of dose) in the urine. Orally administered radiolabelled mycophenolate mofetil results in complete recovery of the administered dose with 93% of the administered dose recovered in the urine and 6% recovered in the feces.
Most (about 87%) of the administered dose is excreted in the urine as MPAG.