Mycophenolic Acid

MPA is a fermentation product of Pénicillium species that was originally shown to have antibacterial, antifungal, and immunosuppressive potential in animal studies (173). To improve the bioavailability of MPA, mycophenolate mofetil (brand name CellCept), the 2-morpholinoethyl ester of MPA was developed for oral and intravenous administration (174). Mycophenolate mofetil received FDA approval for use as an immunosuppressant with corticosteroids and CsA to prevent organ rejection in 1995. The sodium salt of MPA, mycophenolate sodium (brand name Myfortic), has recently become available for oral administration as delayed-release tablets. MPA has primarily replaced azathioprine in organ transplantation. The chemical structure of the active compound MPA and the two parent compounds are shown in Fig. 4.

MPA is a potent non-competitive inhibitor of inosine monophosphate dehydro-genase (IMPDH) enzymatic activity (175). IMPDH is the rate-limiting enzyme in the production of guanosine nucleotides that are required for DNA synthesis and

Mycophenolic Acid

Mycophenolic Acid

Fig. 4. Chemical structures of the active compound mycophenolic acid (MPA), and the two prodrugs, mycophenolate mofetil and mycophenolate sodium. This figure was published in Critical Reviews in Oncology/Hematology, Volume, Taylor AL, Watson CJE, Bradley JA, Immunosuppressive agents in solid organ transplantation: mechanisms of action and therapeutic efficacy, page 29, Copyright Elsevier 2005.

Fig. 4. Chemical structures of the active compound mycophenolic acid (MPA), and the two prodrugs, mycophenolate mofetil and mycophenolate sodium. This figure was published in Critical Reviews in Oncology/Hematology, Volume, Taylor AL, Watson CJE, Bradley JA, Immunosuppressive agents in solid organ transplantation: mechanisms of action and therapeutic efficacy, page 29, Copyright Elsevier 2005.

cellular proliferation. Guanosine nucleotides are synthesized in most cell types using the IMPDH pathway and a separate salvage pathway. However, the salvage pathway is not found in lymphocytes, and MPA blockage of the IMPDH pathway selectively inhibits lymphocyte proliferation (176,177). There are two isoforms of IMPDH and MPA selectively inhibit the type II isoform, which is predominantly expressed by activated and not resting lymphocytes (178).

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