Mechanism of Action of Mycophenolate Mofetil

Mycophenolate mofetil is a prodrug which is rapidly converted to mycophenolic acid (MPA), a potent and reversible uncompetitive inhibitor of inosine monophosphate dehydrogenase (IMPDH). In the de novo purine synthesis pathway, IMPDH is the first of two enzymes responsible for the conversion of inosine monophosphate (IMP) to guanosine monophosphate (GMP), which is normally converted to GDP, GTP, and dGTP. IMPDH is not involved in the salvage pathway of purine biosynthesis. It has been proposed that, since lymphocytes are relatively independent of the salvage pathway of nucleotide biosynthesis, MPA treatment should reduce guanine nucleotide pools in lymphocytes. Measurements show that MPA causes a reduction of GTP and dGTP in lymphocytes but not neutrophils. The consequences of the reduction in guanine nucleotides in lymphocytes, such as the inhibition of DNA synthesis, and GTP-dependent metabolic events, is discussed.