Mycophenolate mofetil is an antimetabolite and potent immunosuppressive agent used as adjunctive therapy in prevention of allograft rejection and in the treatment of serious autoimmune diseases. Mycophenolate therapy can be associated with mild serum enzyme elevations and it has been linked to rare instances of clinically apparent liver injury.
Mycophenolate (mye" koe fen' o late) mofetil (moe' fe til) is an antimetabolite and immunosuppressive agent that is used widely in the prevention of rejection after organ transplantation as well as in management of patients with serious autoimmune diseases. Mycophenolate blocks de novo purine synthesis via noncompetitive inhibition of inosine monophosphate dehydrogenase (IMPDH). Lymphocytes lack the salvage pathway for purine synthesis and are particularly vulnerable to the inhibitory activity of mycophenolate. The result of the IMPDH inhibition is an inhibition of lymphocyte proliferation and function. Mycophenolate mofetil was approved for use in the United States in 1995 and its current indications are for prevention of organ rejection after transplantation. It is also used off label in therapy of active and recalcitrant forms of autoimmune diseases. Mycophenolate is available as capsules of 250 mg and tablets of 500 mg in several generic forms and under the brand name CellCept, and as an oral suspension (200 mg/mL) and a powder for injection (500 mg). It is also available as mycophenolic acid in 180 and 360 mg delayed release tablets under the brand name Myfortic. The typical maintenance dose is 1 to 1.5 grams twice daily. Common side effects include gastrointestinal upset, diarrhea, nausea, headache, fatigue and dizziness.
Serum enzyme elevations occur in a small proportion of patients on mycophenolate mofetil, but the abnormalities are usually mild, asymptomatic and resolve spontaneously or with dose reduction. A small number of cases of clinically apparent liver injury have been reported in patients on mycophenolate. The onset of injury is usually during the first month of therapy and the pattern of serum enzyme elevations is hepatocellular or mixed. The liver injury is usually mild and self-limiting. Autoimmune and immunoallergic features are uncommon.
Mechanism of Injury
Mycophenolate mofetil is a prodrug and undergoes extensive metabolism to mycophenolic acid and to other active metabolites. Idiosyncratic liver injury is likely due to a toxic or immunogenic metabolite.
Outcome and Management
The liver injury due to mycophenolate is usually mild and self limited, resolving by itself or responding rapidly to dose modification or discontinuation. Mycophenolate has not been linked to instances of acute liver failure or vanishing bile duct syndrome. There is no evidence of cross sensitivity to the hepatic injury between mycophenolate and other medications used to prevent rejection such as the calcineurin inhibitors or sirolimus.
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