Mycophenolic acid

Mycophenolic acid (MPA), and also called mycophenolate, is an immunosuppressant medication used to prevent rejection following organ transplantation and to treat Crohn's disease.[3] Specifically it is used following kidney, heart, and liver transplantation.[3] It can be given by mouth or by injection into a vein.[3] It comes as mycophenolate sodium and mycophenolate mofetil.[3]

Mycophenolic acid
Clinical data
Pronunciation/ˌmaɪkoʊfɪˈnɒlɪk/
Trade namesCellCept, Myfortic, others
Other namesMycophenolate sodium, mycophenolate mofetil
AHFS/Drugs.comMonograph
MedlinePlusa601081
License data
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
    Routes of
    administration    		By mouth, intravenous[1]
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Bioavailability72% (sodium),
    94% (mofetil)[2]
    Protein binding82–97%[2]
    MetabolismLiver[2]
    Elimination half-life17.9±6.5 hours[2]
    ExcretionUrine (93%),
    faeces (6%)[2]
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.041.912
    Chemical and physical data
    FormulaC17H20O6
    Molar mass320.34 g/mol g·mol−1
    3D model (JSmol)
     NY (what is this?)  (verify)

    Common side effects include nausea, infections, and diarrhea.[3] Other serious side effects include an increased risk of cancer, progressive multifocal leukoencephalopathy, anemia, and gastrointestinal bleeding.[3] Use during pregnancy may harm the baby.[3] It works by blocking inosine monophosphate dehydrogenase (IMPDH), which is need by lymphocytes to make guanosine.[3]

    Mycophenolic acid was initially discovered by Italian Bartolomeo Gosio in 1893.[4][5] It was rediscovered in 1945 and 1968.[5] It was approved for medical use in the United States in 1995 following the discovery of its immunosuppressive properties in the 1990s.[3][4] It is available as a generic medication.[6] In the United Kingdom it costs the NHS about £14 per month.[6] In the United States this amount is about US$114.[7]

    Medical uses

    Organ transplant

    Mycophenolate is used for the prevention of organ transplant rejection. Mycophenolate mofetil is indicated for the prevention of organ transplant rejection in adults and kidney transplantation rejection in children over 2 years; whereas mycophenolate sodium is indicated for the prevention of kidney transplant rejection in adults. Mycophenolate sodium has also been used for the prevention of rejection in liver, heart, or lung transplants in children older than two years.[8]

    Autoimmune disease

    Mycophenolate is increasingly utilized as a steroid sparing treatment in autoimmune diseases and similar immune-mediated disorders including Behçet's disease, pemphigus vulgaris, immunoglobulin A nephropathy, small vessel vasculitides, and psoriasis.[9] It is also used for retroperitoneal fibrosis along with a number of other medications.[10] Specifically it has also be used for psoriasis not treatable by other methods.[11]

    Its increasing application in treating lupus nephritis has demonstrated more frequent complete response and less frequent complications[9] compared to cyclophosphamide bolus therapy, a regimen with risk of bone marrow suppression, infertility, and malignancy.[12] Further work addressing maintenance therapy demonstrated mycophenolate superior to cyclophosphamide, again in terms of response and side-effects.[12] Walsh proposed that mycophenolate should be considered as a first-line induction therapy for treatment of lupus nephritis in people without kidney dysfunction.[13]

    Comparison to other agents

    Compared with azathioprine it has higher incidence of diarrhea, and no difference in risk of any of the other side effects.[14] Mycophenolic acid is 15 times more expensive than azathioprine.[15] The exact role of mycophenolate vs azathioprine has yet to be conclusively established.

    Adverse effects

    Common adverse drug reactions (≥1% of people) include diarrhea, nausea, vomiting, joint pain; infections, leukopenia, or anemia reflect the immunosuppressive and myelosuppressive nature of the drug. Mycophenolate sodium is also commonly associated with fatigue, headache, cough and/or breathing issues. Intravenous (IV) administration of mycophenolate mofetil is also commonly associated with thrombophlebitis and thrombosis. Infrequent adverse effects (0.1–1% of people) include esophagitis, gastritis, gastrointestinal tract hemorrhage, and/or invasive cytomegalovirus (CMV) infection.[8] More rarely, pulmonary fibrosis or various neoplasia occur: melanoma, lymphoma, other malignancies having an occurrences of 1 in 20 to 1 in 200, depending on the type, with neoplasia in the skin being the most common site.[16][17] Several cases of pure red cell aplasia (PRCA) have also been reported.[18]

    The U.S. Food and Drug Administration (FDA) has issued an alert that people are at increased risk of opportunistic infections, such as activation of latent viral infections, including shingles, other herpes infections, cytomegalovirus, and BK virus associated nephropathy. In addition the FDA is investigating 16 people that developed a rare neurological disease while taking the drug. This is a viral infection known as progressive multifocal leukoencephalopathy; it attacks the brain and is usually fatal.[19]

    MMF and EC-MPS appear to be equal in benefits and safety.[20]

    Pregnancy

    Mycophenolic acid is associated with miscarriage and congenital malformations when used during pregnancy, and should be avoided whenever possible by women trying to get pregnant.[21][22]

    Blood tests

    Among the most common effects of this drug is increased blood cholesterol levels. Other changes in blood chemistry such as hypomagnesemia, hypocalcemia, hyperkalemia, and an increase in blood urea nitrogen (BUN) can occur.[1][23]

    Mechanism of action

    Purines can either be synthesized de novo using ribose 5-phosphate or they can be salvaged from free nucleotides. Mycophenolic acid is potent, reversible, non-competitive inhibitor of inosine-5′-monophosphate dehydrogenase (IMPDH), an enzyme essential to the de novo synthesis of guanosine-5'-monophosphate (GMP) from inosine-5'-monophosphate (IMP).[24] IMPDH inhibition particularly affects lymphocytes since they rely almost exclusively on de novo purine synthesis.[25] In contrast, many other cell types use both pathways, and some cells, such as terminally differentiated neurons, depend completely on purine nucleotide salvage.[26] Thus, use of mycophenolic acid leads to a relatively selective inhibition of DNA replication in T cells and B cells.

    Pharmacology

    Mycophenolate can be derived from the fungi Penicillium stoloniferum, P. brevicompactum and P. echinulatum.[27] Mycophenolate mofetil is metabolised in the liver to the active moiety mycophenolic acid. It reversibly inhibits inosine monophosphate dehydrogenase,[28] 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.[29] Other cells recover purines via a separate salvage pathway and are thus able to escape the effect.[1]

    Mycophenolate is potent and can, in many contexts, be used in place of the older anti-proliferative azathioprine.[30] It is usually used as part of a three-compound regimen of immunosuppressants, also including a calcineurin inhibitor (ciclosporin or tacrolimus) and a glucocorticoid (e.g decadron or prednisone).[31]

    Chemistry

    Mycophenolate mofetil is the morpholino‌ ethyl ester of mycophenolic acid; the ester masks the carboxyl group. Mycophenolate mofetil is reported to have a pKa values of 5.6 for the morpholino moiety and 8.5 for the phenolic group.[32]

    History

    Mycophenolic acid was discovered by Italian medical scientist Bartolomeo Gosio. Gosio collected a fungus from spoiled corn and named it Penicillium glaucum. (The species is now called P. brevicompactum.) In 1893 he found that the fungus had antibacterial activity. In 1896 he isolated crystals of the compound, which he successfully demonstrated as the active antibacterial compound against the anthrax bacterium.[11] This was the first antibiotic that was isolated in pure and crystalline form. But the discovery was forgotten.[33] It was rediscovered by two American scientists C.L. Alsberg and O.M. Black in 1912, and gave the name mycophenolic acid. The compound was eventually demonstrated to have antiviral, antifungal, antibacterial, anticancer, and antipsoriasis activities.[34] Although it is not commercialised as antibiotic due to its adverse effects, its modified compound (ester derivative) is an approved immunosuppressant drug in kidney, heart, and liver transplantations, and is marketed under the brands CellCept (mycophenolate mofetil by Roche) and Myfortic (mycophenolate sodium by Novartis).[35]

    Cellcept was developed by a South African geneticist Anthony Allison and his wife Elsie M. Eugui. In the 1970s while working at the Medical Research Council, Allison investigated the biochemical causes of immunune deficiency in children. He discovered the metabolic pathway involving an enzyme, inosine monophosphate dehydrogenase, which is responsible for undesirable immune response in autoimmune diseases, as well as for immune rejection in organ transplantation. He conceived an idea that if a molecule that could block the enzyme is discovered, then, it would become an immunosuppressive drug that could be used for autoimmune diseases and in organ transplantation. In 1981 he decided to go for drug discovery and approached several pharmaceutical companies, which turned him down one by one as he had no primary knowledge on drug research. However, Syntex liked his plans and asked him to join the company with his wife.[36] He became Vice President for the research. In one of their experiments the Allisons used an antibacterial compound, mycophenolate mofetil, which was abandoned in clinical use due to its adverse effects. They discovered that the compound had immunosuppressive activity.[37][38] They synthesised a chemical variant for increased activity and reduced adverse effects.[39][40][41][42][43] They subsequently demonstrated that it was useful in organ transplantation in experimental rats.[44][45] After successful clinical trials,[46] the compound was approved for use in kidney transplant by the U.S. Food and Drug Administration on 3 May 1995,[47] and was commercialised under the brand name CellCept.[48][49]

    Names

    It was initially introduced as the prodrug mycophenolate mofetil (MMF, trade name CellCept) to improve oral bioavailability. The salt mycophenolate sodium has also been introduced. Enteric-coated mycophenolate sodium (EC-MPS) is an alternative MPA formulation.

    MMF and EC-MPS appear to be equal in benefits and safety.[20]

    Research

    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.[50]

    It is also currently being used as a long-term therapy for maintaining remission of granulomatosis with polyangiitis, though thus far, studies have found it inferior to azathioprine. A combination of mycophenolate and ribavirin has been found to stop infection by and replication of dengue virus in vitro.[51][52]

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