Mycophenolate mofetil/mycophenolic acid

Contraindication Hypersensitivity to mycophenolate mofetil, mycophenolic acid or any components of the drug... 

Mycophenolate mofetil was approved by the FDA in 1995, and enteric-coated mycophenolic acid was approved in 2004. Both agents are considered to be adjunctive immunosuppressants. Mycophenolic acid acts by inhibiting inosine monophosphate deydrogenase, a vital enzyme in the de novo pathway of purine synthesis. Inhibition of this enzyme prevents the proliferation of most cells that are dependent on the de novo pathway for purine synthesis, including T cells.7,11,26-28... 

Mycophenolate mofetil is available in 250 mg capsules and 500 mg tablets, an oral suspension (100 mg/mlL, in cherry syrup), and an injectable.11 Usual doses of mycophenolate mofetil range from 1000 to 3000 mg/day in two to four divided doses. The conversion between oral and IV mycophenolate mofetil is 1 1. Enteric-coated mycophenolic acid is available in 180 and 360 mg tablets. For conversion between mycophenolate mofetil and enteric-coated MPA, 1000 mg mycophenolate mofetil is equivalent to 720 mg enteric-coated MPA.26,29 The recommended starting dose of enteric-coated mycophenolic acid is 720 mg given twice daily.11 It appears that conversion of mycophenolate mofetil to enteric-coated mycophenolic acid is safe, but more studies are needed to determine the exact role of enteric-coated MPA in the immunosuppressive armamentarium. Mycophenolic acid trough concentrations can be monitored, but they are not recommended routinely. 

The most common adverse events associated with these agents are GI (18% to 54%, namely, diarrhea, nausea, vomiting, and gastritis) and myelosuppression (20% to 40%).7,11,26-28 Despite its enteric coating, to date, mycophenolic acid has shown no significant benefit in terms of reduction in GI adverse events compared with mycophenolate mofetil in renal transplant recipients.26... 

Shipkova, M., Armstrong, V.M., Wieland, E., Niedmann, P.D., Schiitz, E., Brenner-WeiC, G., Voihsel, M., Braun, E. and Oellerich, M., Identification of glucoside and carboxyl-linked glucuronide conjugates of mycophenolic acid in plasma of transplant recipients treated with mycophenolate mofetil. Brit. J. Pharmacol., 1999,126, 1075. 

Tablets, delayed-release Mycophenolic acid delayed-release tablets and mycophenolate mofetil tablets and capsules should not be used interchangeably without physician supervision because the rate of absorption following the administration of these 2 products is not equivalent.

Mycophenolate mofetil is used together with cyclosporine and corticosteroids for the prophylaxis of acute organ rejection in patients undergoing allogeneic renal, or hepatic transplants. Compared with azathioprine it is more lymphocyte-specific and is associated with less bone marrow suppression, fewer opportunistic infections and lower incidence of acute rejection. More recently, the salt mycophenolate sodium has also been introduced. Mycophenolate mofetil is rapidly hydrolyzed to mycopheno-lic acid, its active metabolite. Mycophenolic acid is a reversible noncompetitive inhibitor of inosine monophosphate dehydrogenase, an important enzyme for the de novo synthesis of purines. As lymphocytes have little or no salvage pathway for purine... 

Mycophenolate mofetil (MMF, CellCept) is an ester prodrug of mycophenolic acid (MPA), a Penicillium-de-rived immunosuppressive agent (see Chapter 57) that blocks de novo purine synthesis by noncompetitively inhibiting the enzyme inosine monophosphate dehydrogenase. MPA preferentially suppresses the proliferation of cells, such as T and B lymphocytes, that lack the purine salvage pathway and must synthesize de novo... 

Mycophenolate mofetil, a semisynthetic derivative of mycophenolic acid, isolated from the mould PenicilUum glaucum is used in kidney and liver transplant patient. Another newer compound mizoribine is used in kidney transplantation. 

Mycophenolate mofetil (MMF) is converted to mycophenolic acid, the active form of the drug. The active product inhibits cytosine monophosphate dehydrogenase and, secondarily, inhibits T-cell lymphocyte proliferation downstream, it interferes with leukocyte adhesion to endothelial cells through inhibition of E-selectin, P-selectin, and intercellular adhesion molecule 1. MMF s pharmacokinetics and toxicities are discussed in Chapter 55. 

Mycophenolate mofetil (MMF) is a semisynthetic derivative of mycophenolic acid, isolated from the mold Penicillium glaucus. In vitro, it inhibits T- and B-lymphocyte responses, including mitogen and mixed lymphocyte responses, probably by inhibition of de novo synthesis of purines. Mycophenolate mofetil is hydrolyzed to mycophenolic acid, the active immunosuppressive moiety it is synthesized and administered as MMF to enhance bioavailability. 

Mycophenolate mofetil is available in both oral and intravenous forms. The oral form is rapidly metabolized to mycophenolic acid. Although the cytochrome P450 system is not involved, some drug interactions still occur. Plasma drug levels are frequently monitored, similar to the calcineurin inhibitors and PSIs. 

The metabolism of mycophenolate is altered by coadministration with cyclosporine. Mycophenolic acid (MPA) levels are lower when mycophenolate mofetil is compared with cyclosporine. Lower doses should be considered in recipients receiving tacrolimus or steroids done without a calcineurin inhibitor. 

Mycophenolic acid (MPA) was isolated from cultures of Penicillium spp. in 1896 and was purified in 1913. Initially the compound was studied for its antifungal and antibacterial effects and later for its antitumor effects. Many years later, its immunosuppressive activities were recognized and after further developmental work, an ester prodrug mycophenolate mofetil was developed, which was approved by the United States Food and Drug Administration for the prevention of acute renal allograft rejection in 1995 and for heart transplant recipients in 1998. Mycophenolate mofetil is a cytotoxic agent now used for immunosuppressive therapy and is the mofetil ester of MPA, which is the active immunosuppressive agent. 

Mycophenolic acid (Figure 3.36) is produced by fermentation cultures of the fungus Penicillium brevicompactum. It has been known for many years to have antibacterial, antifungal, antiviral, and antitumour properties. It has recently been introduced into medicine as an immunosuppressant drug, to reduce the incidence of rejection of transplanted organs, particularly kidney and heart transplants. It is formulated as the /V-morpholinoethyl ester mycophenolate mofetil (Figure 3.37), which is metabolized after ingestion to mycophenolic... 

Mycophenolic acid may be obtained by the fermentation broth of Pennicillium brevicompactum. The synthesis of Mycophenolate mofetil (Patent U.S. 4,753,935). The mixture of Mycophenolic acid (32.0 g), thionyl chloride (25.0 ml) and DMF (0.3 ml) in dichloromethane (250 ml) was stirred at room temperature for 3 hours, after which the volatile components were removed under vacuum to afford mycophenolic acid chloride as an oil. The mycophenolic acid chloride oil was dissolved in dichloromethane (50.0 ml) and added to the chilled solution of morpholinoethanol (30.5 ml) in dichloromethane (250 ml). After stirring for 90 min at 4°C, the reaction mixture was washed with water and then with aqueous sodium bicarbonate. The organic solution was dried with sodium sulfate and evaporated to yield Mycophenolate mofetil morpholinoethyl E-6-(l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate (melting point 93-94°C). 

Zucker K, Tsaroucha A, Olson L, et al. Evidence that tacrolimus augments the bioavailahility of mycophenolate mofetil through the inhibition of mycophenolic acid glucuronidation. Ther Drug Monit 1999 21(l) 35-43. 

Mycophenolate mofetil is the 2-moiphohnoethyl ester of mycophenolic acid (MPA). It is a prodrug that is rapidly hydrolyzed to the active form, mycophenolic acid. Mycophenolic acid is a selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). IMPDH is an important enzyme in the de novo pathway of purine nucleotide synthesis. This pathway is very important in B and T lymphocytes for proliferation. Other cells can use salvage pathways. Therefore MPA inhibits lymphocyte proliferation and functions. The mofetil ester is first converted to MPA which then is metabolized to an inactive glucuronide (Alhson and Eugui, 2000). MPA has a half-hfe of about 16 hours (Fulton and Markham, 1996). 

Mycophenolate mofetil, the morphohnoethyl ester of mycophenolic acid (rINN), is an antimetabohte that interferes with the synthesis of nucleic acids and selectively inhibits the proliferation of T and B lymphocytes. It has been used to treat psoriasis and to prevent acute renal allograft rejection in combination with ciclosporin and glucocorticoids. 

In 52 patients taking mycophenolate mofetil 1 g bd, prednisone, and ciclosporin to a target blood concentration of 125-175 ng/ml for 6 months after transplantation, withdrawal of ciclosporin resulted in almost a doubling of mycophenolic acid trough concentrations (43). 

Hubner GI, Eismann R, Sziegoleit W. Drug interaction between mycophenolate mofetil and tacrolimus detectable within therapeutic mycophenolic acid monitoring in renal transplant patients. Ther Drug Monit 1999 21(5) 536-9. 

Mycil chlorphenesin tolnafitate. mycophenolate mofetil [usan] (CellCept ) is converted in vivo to n cophenolic add, which has antimetabolite cytotoxic properties. It shows experimental activity as an ANTICANCER and ANTIVIRAL AGENT. It may be clinically useful in treating psoriasis and as an ANTU.EISHMANIAL. It shows IMMUNOSUPPRESSANT properties, and is used in the prophylaxis of acute kidney rejection, mycophenolic acid [ban, inn, usan] is usually... 

Mycophenolic acid (MPA) was first isolated from the Penicillin glaucum mold. It was first smdied as an antibiotic but later was found to have immunosuppressive properties. Mycophenolate mofetil (MMF) the morpholinoethyl ester of MPA appears to be a specific immunosuppressant for lymphocytes, resulting in fewer adverse effects than azathioprine, making it the preferred agent over azathioprine. 

Mycophenolate mofetil, a semisynthetic morpholinoester of my-cophenolic acid, initially was used to prevent acute rejection after renal and cardiac transplantation, but it is now used as part of combination therapy in moderate to severe psoriasis and other autoimmune dermatoses. It reversibly blocks de novo synthesis of guanine nucleotides required for DNA and RNA synthesis. The drug has been shown to have a speciflc lymphocyte antiproliferative effect. Oral mycophenolate mofetil, as well as topical mycophenolic acid, may undergo further clinical studies to establish efficacy in the treatment of patients with severe psoriasis. " ... 

Commonly reported adverse effects of mycophenolate mofetil include gastrointestinal toxicity (diarrhea, nausea, and vomiting), hematologic effects (anemia, neutropenia, and thrombocytopenia), and an increased incidence of viral and bacterial infections. Lym-phoproliferative disease or lymphoma has developed in up to 1 % of patients who received mycophenolic acid with other immunosuppressive agents. 

Asif, A. R. et al., Proteins identified as targets of the acyl glucuronide metabolite of mycophenolic acid in kidney tissue from mycophenolate mofetil treated rats, Biochimie, 89 (3), 393, 2007. 

Mycophenolate mofetil (Cellcept) is the 2-morpholino-ethyl ester of mycophenolic acid (MPA). 

Mycophenolate mofetil (Cellcept) is an immunosuppressant approved for prophylaxis of organ rejection in patients with renal, cardiac, and hepatic transplants. Myco-phenolic acid, the active derivative of mycophenolate mofetil, inhibits the enzyme inosine monophosphatase dehydrogenase (IMPDH), thereby depleting guanosine nucleotides essential for DNA and RNA synthesis. Moreover, mycophenolic acid is a fivefold more potent inhibitor of the type 11 isoform of IMPDH found in activated B- and T-lymphocytes and thus functions as a specific inhibitor of T- and B-lymphocyte activation and proliferation. The drug also may enhance apoptosis. 

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