Mycophenolic acid

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Mycophenolic acid
280px
Systematic (IUPAC) name
(4E)-​6-​(4-​hydroxy-​6-​methoxy-​7-​methyl-​3-​oxo-​1,​3-​dihydro-​2-​benzofuran-​5-​yl)-​4-​methylhex-​4-​enoic acid
Clinical data
[[Regulation of therapeutic goods |Template:Engvar data]]
Pregnancy
category
Routes of
administration
Oral, IV
Legal status
Legal status
  • S4 (Au), POM (UK), ℞-only (U.S.)
Pharmacokinetic data
Bioavailability 94% (mofetil), 72% (sodium)
Protein binding 97%
Metabolism Hepatic
Biological half-life 16–18 hours
Excretion Renal 93%
Identifiers
CAS Number 24280-93-1
ATC code L04AA06 (WHO)
PubChem CID 446541
Chemical data
Formula C17H20O6
Molar mass 320.34 g·mol−1[[Script error: No such module "String".]]
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Mycophenolic acid (INN) (pronounced /ˌmaɪkoʊfɨˈnɒlɪk/) or mycophenolate is an immunosuppressant drug used to prevent rejection in organ transplantation. It was initially marketed as the prodrug mycophenolate mofetil (MMF) to improve oral bioavailability. More recently, the salt mycophenolate sodium has also been introduced. Mycophenolic acid is commonly marketed under the trade names CellCept (mycophenolate mofetil; Roche) and Myfortic (mycophenolate sodium; Novartis).

Clinical use

Indications

In general, mycophenolate is used for the prevention of organ transplant rejection. Mycophenolate mofetil is indicated for the prevention of organ transplant rejection in adults and renal transplant rejection in children over 2 years; whereas mycophenolate sodium is indicated for the prevention of renal transplant rejection in adults. Mycophenolate sodium has also been used for the prevention of rejection in liver, heart, and/or lung transplants in children >2 years.[1]

An immunosuppressant that has drastically decreased the incidence of acute rejection in solid transplant recipients, mycophenolate is increasingly utilized as a steroid sparing treatment in immune-mediated disorders including immunoglobulin A nephropathy, small vessel vasculitides, and psoriasis.[2]

Its increasing application in treating lupus nephritis has demonstrated more frequent complete response and less frequent complications [2] compared to cyclophosphamide bolus therapy, a regimen with risk of bone marrow suppression, infertility, and malignancy.[3] Further work addressing maintenance therapy demonstrated mycophenolate superior to cyclophosphamide, again in terms of response and side-effects.[3] Walsh et al. even propose that mycophenolate should be considered as a first-line induction therapy for treatment of lupus nephritis in patients without renal dysfunction,[4] suggesting that mycophenolate will be encountered more frequently in medical practice.

Comparison to other agents

Compared with azathioprine it has significantly higher incidence of diarrhoea, and no difference in risk of any of the other side effects.[5] Mycophenolic acid is 15 times more expensive than azathioprine[6] The exact role of mycophenolate vs azathioprine has yet to be conclusively established. In long-term immunosuppression, it may be used to avoid calcineurin inhibitors or steroids.

Potential future uses

Mycophenolate mofetil is beginning to be used in the management of auto-immune disorders such as idiopathic thrombocytopenic purpura (ITP), systemic lupus erythematosus (SLE), scleroderma (Systemic sclerosis or SSc) and pemphigus vulgaris (PV) with success for some patients.[7]

It is also currently being used as a long-term therapy for maintaining remission of C-ANCA positive (Wegener's) granulomatosis. A combination of mycophenolate and ribavirin has been found to stop infection by and replication of dengue virus in vitro.[8][9]

Adverse effects

Common adverse drug reactions (≥1% of patients) associated with mycophenolate therapy include diarrhoea, nausea, vomiting, infections, leukopenia, and/or anemia. Mycophenolate sodium is also commonly associated with fatigue, headache, and/or cough. Intravenous (IV) administration of mycophenolate mofetil is also commonly associated with thrombophlebitis and thrombosis. Infrequent adverse effects (0.1–1% of patients) include esophagitis, gastritis, gastrointestinal tract hemorrhage, and/or invasive cytomegalovirus (CMV) infection.[1] Several cases of pure red cell aplasia (PRCA) have also been reported.[10]

The U.S. Food and Drug Administration (FDA) has issued an alert that patients on mycophenolate mofetil and mycophenolic acid are at increased risk of opportunistic infections, such as activation of latent viral infections, including BK-virus associated nephropathy. In addition the FDA is investigating 16 patients that developed a rare neurological disease while taking the drug. The neurological condition known as progressive multifocal leukoencephalopathy attacks the brain and central nervous system and is usually fatal.[11]

Mycophenolic acid is associated with miscarriage and congenital malformations when used during pregnancy, and should be avoided whenever possible by women trying to conceive.[12][13]

Pharmacology

Mycophenolate is derived from the fungus Penicillium stoloniferum. Mycophenolate mofetil is metabolised in the liver to the active moiety mycophenolic acid. It inhibits inosine monophosphate dehydrogenase, the enzyme that controls the rate of synthesis of guanine monophosphate in the de novo pathway of purine synthesis used in the proliferation of B and T lymphocytes.[14]

Mycophenolate is potent and can be used in place of the older anti-proliferative azathioprine. It is usually used as part of a three-compound regimen of immunosuppressants, also including a calcineurin inhibitor (cyclosporin or tacrolimus) and prednisolone.

References

File:Mycophenolate mofetil.svg
Mycophenolate mofetil

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External links

de:Mycophenolsäure

es:Ácido micofenólico hu:Mikofenolát-mofetil nl:Mycofenolzuur ja:ミコフェノール酸モフェチル pl:Kwas mykofenolowy ru:Микофенолата мофетил

vi:Mycophenolic
  1. 1.0 1.1 Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3[page needed]
  2. 2.0 2.1 Moore RA, Derry S (2006). "Systematic review and meta-analysis of randomised trials and cohort studies of mycophenolate mofetil in lupus nephritis". Arthritis Research & Therapy. 8 (6): R182. doi:10.1186/ar2093. PMC 1794528Freely accessible. PMID 17163990. 
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  6. Remuzzi G, Lesti M, Gotti E; et al. (2004). "Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial". Lancet. 364 (9433): 503–12. doi:10.1016/S0140-6736(04)16808-6. PMID 15302193. 
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  8. Diamond MS, Zachariah M, Harris E (2002). "Mycophenolic acid inhibits dengue virus infection by preventing replication of viral RNA". Virology. 304 (2): 211–21. doi:10.1006/viro.2002.1685. PMID 12504563. 
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  10. "CellCept (mycophenolate mofetil) August 2009". U.S. Food and Drug Administration. August 14, 2009. Retrieved 2009-08-21. 
  11. [1][dead link]
  12. [2][dead link]
  13. "MedWatch Safety Alerts for Human Medical Products". Fda.gov. 2010-03-22. Retrieved 2010-07-28. 
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