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Pharmacology: Mycophenolate mofetil, the 2-morpholinoethyl ester of mycophenolic acid (MPA), is an immunosuppressive agent. Mycophenolate mofetil is a prodrug that has little pharmacologic activity until hydrolyzed in vivo to mycophenolic acid (MPA), the pharmacologically active metabolite. MPA is a potent, selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. MPA has more potent cytostatic effects on lymphocytes than on other cells.
Pharmacokinetics: Absorption: Mycophenolate mofetil is well absorbed following oral administration, having an absolute bioavailability of approximately 94% (based on mycophenolic acid and undergoes complete presystemic metabolism to the active metabolite, MPA. Mycophenolate mofetil can be measured systemically during intravenous infusion; however, after oral administration it is below the limit of quantitation (0.4 μg/mL). Food had no effect on the extent of absorption (MPA AUC) of mycophenolate mofetil 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.
Distribution: Secondary increases in plasma MPA concentration are usually observed at approximately 6-12 hours post-dose, consistent with enterohepatic recirculation.
At clinically relevant concentrations, MPA is 97% bound to plasma albumin.
Metabolism: MPA is conjugated primarily with glucuronyl transferase to form the phenolic glucuronide of MPA (MPAG), which is not pharmacologically active. In vivo, MPAG is converted to free MPA via enterohepatic recirculation.
Elimination: 93% of an orally administered dose of mycophenolate mofetil is excreted in urine (about 87% mainly as the phenolic glucuronide of MPA and negligible amount of less than 1% of dose is excreted as MPA) and 6% is excreted in faeces. At clinically encountered concentrations MPA and MPAG are not removed by hemodialysis. However, at high MPAG concentrations (>100 μg/mL), small amounts of MPAG are removed. By interfering with enterohepatic circulation of the drug, bile acid sequestrants, such as cholestyramine, reduce MPA AUC.
