From mice to man: the preclinical history of mycophenolate mofetil.
In vitro studies demonstrating that mycophenolic acid (MPA) held promise as a powerful immunosuppressant led to a series of in vivo studies to further evaluate this interesting new agent. Experiments in mice showed that MPA had powerful lymphocyte-selective immunosuppressive effects. A prodrug of MPA, mycophenolate mofetil (MMF), was developed to improve bioavailability on oral administration. Numerous tests demonstrated that MMF, alone or in combination with other immunosuppressives, prolonged allograft survival of various organs in several species and may be useful for reversing ongoing rejection. MMF also was found to be useful in prolonging xenograft survival. These animal experiments indicated that MMF had the benefit of relatively low toxicity and a good safety profile and drove early clinical trials of MMF. These trials showed that MMF is relatively safe and well tolerated in man and is of potential use for the prevention and treatment of acute allograft rejection. This article describes the preclinical history of the development of MMF, concentrating on the animal experiments and phase I and II trials that preceded the large-scale clinical testing of this new immunosuppressant.
Sollinger
H W
HW
Department of Surgery, University of Wisconsin School of Medicine, Madison 53792, USA.
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004341:Drug Evaluation; D004353:Drug Evaluation, Preclinical; D006084:Graft Rejection / Q000188:drug therapy / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects; D051379:Mice; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D011355:Prodrugs / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D011355:Prodrugs; D009173:Mycophenolic Acid