Mycophenolic acid

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Mycophenolic acid is an immunosuppressant medication used to prevent rejection following organ transplantation and to treat autoimmune conditions such as Crohn's disease and lupus.<ref name="DCruz"></ref><ref name=AHFS2019/> Specifically it is used following kidney, heart, and liver transplantation.<ref name=AHFS2019/> It can be given by mouth or by injection into a vein.<ref name=AHFS2019/> It comes as mycophenolate sodium and mycophenolate mofetil.<ref name=AHFS2019/>

Common side effects include nausea, infections, and diarrhea.<ref name=AHFS2019/> Other serious side effects include an increased risk of cancer, progressive multifocal leukoencephalopathy, anemia, and gastrointestinal bleeding.<ref name=AHFS2019/> Use during pregnancy may harm the baby.<ref name=AHFS2019/> It works by blocking inosine monophosphate dehydrogenase (IMPDH), which is needed by lymphocytes to make guanosine.<ref name=AHFS2019/>

Mycophenolic acid was initially discovered by Italian Bartolomeo Gosio in 1893.<ref name=Sch2011>Template:Cite book</ref><ref name=Las2011>Template:Cite book</ref> It was rediscovered in 1945 and 1968.<ref name=Las2011/> It was approved for medical use in the United States in 1995 following the discovery of its immunosuppressive properties in the 1990s.<ref name=AHFS2019>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=Sch2011/> It is available as a generic medication.<ref name=BNF76>Template:Cite book</ref> In 2022, it was the 227th most commonly prescribed medication in the United States, with more than 1Template:Nbspmillion prescriptions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref name="AMH2006">Template:Cite bookTemplate:Page needed</ref>

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.<ref name="Moore">Template:Cite journal</ref> It is also used for retroperitoneal fibrosis along with a number of other medications.<ref>Template:Cite book</ref> Specifically it has also been used for psoriasis not treatable by other methods.<ref name=silverman>Template:Cite journal</ref>

Its increasing application in treating lupus nephritis has demonstrated more frequent complete response and less frequent complications<ref name="Moore"/> compared to cyclophosphamide bolus therapy, a regimen with risk of bone marrow suppression, infertility, and malignancy.<ref name="DCruz">Template:Cite journal</ref> Further work addressing maintenance therapy demonstrated mycophenolate superior to cyclophosphamide, again in terms of response and side-effects.<ref name="DCruz"/><ref>Template:Cite journal</ref> Walsh proposed that mycophenolate should be considered as a first-line induction therapy for treatment of lupus nephritis in people without kidney dysfunction.<ref name="Walsh">Template:Cite journal</ref>

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 in transplant patients.<ref>Template:Cite journal</ref> Mycophenolic acid is 15 times more expensive than azathioprine.<ref>Template:Cite journal</ref>

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.<ref name="AMH2006"/> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>Template:Nonspecific Several cases of pure red cell aplasia (PRCA) have also been reported.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

The U.S. Food and Drug Administration (FDA) 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 investigatingTemplate:When 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref name="Austria-Codex">Template:Cite book</ref><ref>Drugs.com: Mycophenolic acid Template:Drugs.com</ref>

Mechanism of action

Purines (including the nucleosides guanosine and adenosine) can either be synthesized de novo using ribose 5-phosphate or they can be salvaged from free nucleotides. Mycophenolic acid is a 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).<ref>Template:Cite book</ref> IMPDH inhibition particularly affects lymphocytes since they rely almost exclusively on de novo purine synthesis.<ref>Template:Cite book</ref> In contrast, many other cell types use both pathways, and some cells, such as terminally differentiated neurons, depend completely on purine nucleotide salvage.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> Mycophenolate mofetil is metabolised in the liver to the active moiety mycophenolic acid. It reversibly inhibits inosine monophosphate dehydrogenase,<ref name="Fulton">Template:Cite journal</ref> 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.<ref name=pmid8588241>Template:Cite journal</ref> Other cells recover purines via a separate salvage pathway and are thus able to escape the effect.<ref name="Austria-Codex"/>

Mycophenolate is potent and can, in many contexts, be used in place of the older anti-proliferative azathioprine.<ref>Template:Cite journal</ref> 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. dexamethasone or prednisone).<ref name="pmid24673712">Template:Cite journal</ref>

Chemistry

File:Mycophenolate mofetil structure.png

Mycophenolate mofetil, a prodrug form of mycophenolic acid used in medicine

Mycophenolate mofetil is the morpholinoTemplate:Zwnj ethyl ester of mycophenolic acid; the ester masks the carboxyl group.<ref name="pmid8918281">Template:Cite journal</ref> Mycophenolate mofetil is reported to have a pKa values of 5.6 for the morpholino moiety and 8.5 for the phenolic group.

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.Template:Cn) 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.<ref name=silverman/> This was the first antibiotic that was isolated in pure and crystalline form. But the discovery was forgotten.<ref>Template:Cite book</ref> It was rediscovered by two American scientists C.L. Alsberg and O.M. Black in 1912, and given the name mycophenolic acid. The compound was eventually demonstrated to have antiviral, antifungal, antibacterial, anticancer, and antipsoriasis activities.<ref>Template:Cite journal</ref> 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).<ref>Template:Cite journal</ref>

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 immune 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 of drug research. However, Syntex liked his plans and asked him to join the company with his wife.<ref name=watt>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> They synthesised a chemical variant for increased activity and reduced adverse effects.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> They subsequently demonstrated that it was useful in organ transplantation in experimental rats.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> After successful clinical trials,<ref>Template:Cite journal</ref> the compound was approved for use in kidney transplant by the U.S. Food and Drug Administration on 3 May 1995,<ref name=fda>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and was sold under the brand name Cellcept.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It was approved for use in the European Union in February 1996.<ref name="CellCept EPAR">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Names

It was initially introduced as the prodrug mycophenolate mofetil (MMF, brand 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.<ref name=MR2015>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref>

It is also being used as a long-term therapy for maintaining remission of granulomatosis with polyangiitis, though thus far, studies have found it inferior to azathioprine.Template:Citation needed A combination of mycophenolate and ribavirin has been found to stop infection by and replication of dengue virus in vitro.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> It has also shown promising antiviral activity against MERS, especially in combination with interferon.<ref>Template:Cite journal</ref>

Preliminary data suggest that mycophenolate mofetil might have benefits in people with multiple sclerosis. However the evidence is insufficient to determine the effects as an add‐on therapy for interferon beta-1a in people with RRMS.<ref>Template:Cite journal</ref>