[Pharmacological profiles of mycophenolate mofetil (CellCept), a new immunosuppressive agent].
Mycophenolate mofetil (MMF, CellCept), a semisynthetic derivative of mycophenolic acid (MPA) produced by a fungus, is an inhibitor of the inosine monophosphate dehydrogenase (IMPDH) enzyme (IC50 = 25 nM) that catalyzes the synthesis of guanosine monophosphate (GMP) from inosine. GMP is an essential nucleoside for purine synthesis during cell division. As T and B-lymphocytes almost exclusively use the de novo pathway of purine synthesis, these cells are particularly sensitive to the inhibitory action of MMF. It has a mechanism of action distinct from cyclosporine and tacrolimus. Although MMF does not affect cytokine production, by inhibiting the rate-limiting enzyme IMPDH in the de novo synthesis of purines, it inhibits the proliferation of T and B-lymphocytes, the production of antibodies, and the generation of cytotoxic T lymphocytes. Reversal of acute allograft rejection and increased survival of kidney, heart and bone marrow cell allograft has been shown in several animal studies. Moreover, it was suggested that MMF combined with CsA prevented the acute rejection, and approximately half of the animals became long-term survivors. The Ministry of Health and Welfare approved MMF in 1999 for use for rejection treatment in renal transplantation based on several prospective, randomized and blind efficacy trials.
Nippon Roche Research Center, Nippon Roche K.K., 200 Kajiwara, Kamakura City, Kanagawa 247-8530, Japan. yukihiko.yashima@roche.com
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Yashima
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Ohgane
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006084:Graft Rejection / Q000517:prevention & control; D006157:Guanosine Monophosphate / Q000096:biosynthesis / Q000502:physiology; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016030:Kidney Transplantation; D008214:Lymphocytes / Q000276:immunology; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D011355:Prodrugs / Q000494:pharmacology / Q000627:therapeutic use; D011687:Purines / Q000096:biosynthesis; D016032:Randomized Controlled Trials as Topic
D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D011355:Prodrugs; D011687:Purines; D006157:Guanosine Monophosphate; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid; C030985:purine