Mycophenolic acid

{{Short description|Immunosuppressant medication}} {{Use dmy dates|date=May 2024}} {{cs1 config |name-list-style=vanc |display-authors=6}} {{Infobox drug | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 476995047 | image = Mycophenolicacid.svg | image_class = skin-invert-image | width = 200 | alt = | image2 = Mycophenolic acid 3D.png | image_class2 = bg-transparent | width2 = | alt2 = | caption = Molecular structure of mycophenolic acid | AAN = Mycophenolate mofetil | USAN = Mycophenolate mofetil

| pronounce = {{IPAc-en|ˌ|m|aɪ|k|oʊ|f|ᵻ|ˈ|n|ɒ|l|ɪ|k}} | tradename = Cellcept, Myfortic, Myhibbin, others | Drugs.com = {{drugs.com|monograph|mycophenolate}} | MedlinePlus = a601081 | DailyMedID = Mycophenolate mofetil | pregnancy_AU = D | pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Mycophenolate mofetil (Cellcept) Use During Pregnancy | website=Drugs.com | date=24 January 2020 | url=https://www.drugs.com/pregnancy/mycophenolate-mofetil.html | access-date=6 April 2020 | archive-date=28 October 2019 | archive-url=https://web.archive.org/web/20191028143929/https://www.drugs.com/pregnancy/mycophenolate-mofetil.html | url-status=live }}</ref> | pregnancy_category = | routes_of_administration = By mouth, intravenous<ref name="Austria-Codex"/> | caption2 = 3D representation of mycophenolic acid | class = | ATC_prefix = L04 | ATC_suffix = AA06 | ATC_supplemental =  | legal_AU = S4 | legal_AU_comment = <ref name="CellCept PI">{{Cite web |url=https://www.guildlink.com.au/gc/ws/ro/pi.cfm?product=ropccept10215 |title=Cellcept (mycophenolate mofetil) | work = Australian Product Information | date = 30 November 2021 |access-date=8 January 2023 |archive-date=8 January 2023 |archive-url=https://web.archive.org/web/20230108233340/https://www.guildlink.com.au/gc/ws/ro/pi.cfm?product=ropccept10215 |url-status=live }}</ref><ref>{{cite web | title=Pharmacor mycophenolate, mycocell, alcept (Pharmacor Pty Ltd) | website=Therapeutic Goods Administration (TGA) | date=11 November 2022 | url=https://www.tga.gov.au/resources/prescription-medicines-registrations/pharmacor-mycophenolate-mycocell-alcept-pharmacor-pty-ltd | access-date=29 April 2023 | archive-date=18 March 2023 | archive-url=https://web.archive.org/web/20230318050718/https://www.tga.gov.au/resources/prescription-medicines-registrations/pharmacor-mycophenolate-mycocell-alcept-pharmacor-pty-ltd | url-status=live }}</ref> | legal_BR =  | legal_BR_comment = | legal_CA = Rx-only | legal_CA_comment = <ref>{{cite web | title=Myfortic Product information | website=Health Canada | date=11 February 2005 | url=https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=75000 | access-date=16 February 2025}}</ref> | legal_DE =  | legal_DE_comment = | legal_NZ =  | legal_NZ_comment = | legal_UK = POM | legal_UK_comment = <ref>{{cite web | title=Cellcept 1g/5ml powder for oral suspension - Summary of Product Characteristics (SmPC) | website=(emc) | date=27 February 2020 | url=https://www.medicines.org.uk/emc/product/1569/smpc | access-date=22 October 2020 | archive-date=25 September 2020 | archive-url=https://web.archive.org/web/20200925163745/https://www.medicines.org.uk/emc/product/1569/smpc | url-status=live }}</ref><ref>{{cite web | title=Cellcept 250mg Capsules - Summary of Product Characteristics (SmPC) | website=(emc) | date=17 June 2020 | url=https://www.medicines.org.uk/emc/product/1102/smpc | access-date=22 October 2020 | archive-date=25 September 2020 | archive-url=https://web.archive.org/web/20200925173738/https://www.medicines.org.uk/emc/product/1102/smpc | url-status=live }}</ref><ref>{{cite web | title=Cellcept 500mg Film-Coated Tablets - Summary of Product Characteristics (SmPC) | website=(emc) | url=https://www.medicines.org.uk/emc/product/1103/smpc | access-date=22 October 2020 | archive-date=25 September 2020 | archive-url=https://web.archive.org/web/20200925171640/https://www.medicines.org.uk/emc/product/1103/smpc | url-status=live }}</ref> | legal_US = Rx-only | legal_US_comment = <ref>{{cite web | title=Cellcept- mycophenolate mofetil tablet, film coated Cellcept- mycophenolate mofetil capsule Cellcept- mycophenolate mofetil hydrochloride injection, powder, lyophilized, for solution Cellcept- mycophenolate mofetil powder, for suspension | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=37241e87-4af4-4dc3-a1aa-ea6f20d8dc40 | access-date=23 October 2020 | archive-date=24 October 2020 | archive-url=https://web.archive.org/web/20201024084207/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=37241e87-4af4-4dc3-a1aa-ea6f20d8dc40 | url-status=live }}</ref><ref name="Myhibbin FDA label">{{cite web | title=Myhibbin- mycophenolate mofetil suspension | website=DailyMed | date=7 May 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d9af72d6-7b3e-4c08-94b9-1d8b499cb7f9 | access-date=16 June 2024}}</ref> | legal_EU = Rx-only | legal_EU_comment = <ref name="CellCept EPAR" /> | legal_UN =  | legal_UN_comment = | legal_status = Rx-only

| bioavailability = 72% (sodium),<br/>94% (mofetil)<ref name = TGA>{{cite web|title=Cellcept|work=TGA eBusiness Services|publisher=Roche Products Pty Limited|date=13 December 2012|access-date=25 February 2014|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-03448-3|format=PDF|archive-date=8 July 2020|archive-url=https://web.archive.org/web/20200708204033/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-03448-3|url-status=live}}</ref> | protein_bound = 82–97%<ref name = TGA/> | metabolism = Liver<ref name = TGA/> | metabolites = | onset = | elimination_half-life = 17.9±6.5 hours<ref name = TGA/> | duration_of_action = | excretion = Urine (93%),<br/>faeces (6%)<ref name = TGA/>

| CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 24280-93-1 | CAS_supplemental = {{CAS|128794-94-5}} (mofetil ester),{{CAS|37415-62-6}} (sodium salt) | PubChem = 446541 | IUPHAR_ligand = 6832 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB01024 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 393865 | UNII_Ref = {{fdacite|changed|FDA}} | UNII = HU9DX48N0T | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D05096 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 168396 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 866 | NIAID_ChemDB = | PDB_ligand = | synonyms = MPA, Mycophenolate sodium

| IUPAC_name = (4''E'')-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methylhex-4-enoic acid | C = 17 | H = 20 | O = 6 | index_label = mycophenolic acid | SMILES = O=C1OCc2c1c(O)c(c(OC)c2C)C\C=C(/C)CCC(=O)O | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C17H20O6/c1-9(5-7-13(18)19)4-6-11-15(20)14-12(8-23-17(14)21)10(2)16(11)22-3/h4,20H,5-8H2,1-3H3,(H,18,19)/b9-4+ | StdInChI_comment = | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = HPNSFSBZBAHARI-RUDMXATFSA-N | index2_label = mofetil ester | SMILES2 = COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)OCCN1CCOCC1)C(=O)OC2 | StdInChI2 = 1S/C23H31NO7/c1-15(5-7-19(25)30-13-10-24-8-11-29-12-9-24)4-6-17-21(26)20-18(14-31-23(20)27)16(2)22(17)28-3/h4,26H,5-14H2,1-3H3/b15-4+ | StdInChIKey2 = RTGDFNSFWBGLEC-SYZQJQIISA-N | density = | density_notes = | melting_point = 141 | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}

'''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>{{cite book | vauthors = Schiff ER, Maddrey WC, Sorrell MF |title=Schiff's Diseases of the Liver |date=2011 |publisher=John Wiley & Sons |isbn=978-1-119-95048-6 |page=PT3219 |url=https://books.google.com/books?id=HsxFSx_B4sUC&pg=PT3219 |language=en |access-date=23 September 2020 |archive-date=29 April 2023 |archive-url=https://web.archive.org/web/20230429051159/https://books.google.com/books?id=HsxFSx_B4sUC&pg=PT3219 |url-status=live }}</ref><ref name=Las2011>{{cite book | vauthors = Laskin AI, Bennett JW, Gadd GM |author3-link=Geoffrey Michael Gadd |title=Advances in Applied Microbiology |date=2001 |publisher=Gulf Professional Publishing |isbn=978-0-12-002648-7 |page=236 |url=https://books.google.com/books?id=0WqTtYOVPTMC&pg=PA236 |language=en |access-date=23 September 2020 |archive-date=29 April 2023 |archive-url=https://web.archive.org/web/20230429051159/https://books.google.com/books?id=0WqTtYOVPTMC&pg=PA236 |url-status=live }}</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>{{cite web |title=Mycophenolate Monograph for Professionals |url=https://www.drugs.com/monograph/mycophenolate.html |website=Drugs.com |access-date=28 October 2019 |language=en |archive-date=21 April 2020 |archive-url=https://web.archive.org/web/20200421004944/https://www.drugs.com/monograph/mycophenolate.html |url-status=live }}</ref><ref name=Sch2011/> It is available as a generic medication.<ref name=BNF76>{{cite book|title=British national formulary: BNF 76|date=2018|publisher=Pharmaceutical Press|isbn=978-0-85711-338-2|pages=826–827|edition=76}}</ref> In 2022, it was the 227th most commonly prescribed medication in the United States, with more than 1{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Mycophenolate Mofetil Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/MycophenolateMofetil | access-date = 30 August 2024 }}</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">{{cite book | veditors = Rossi S | title = Australian Medicines Handbook | title-link = Australian Medicines Handbook | date = 2006 | location = Adelaide | publisher = Australian Medicines Handbook | isbn = 978-0-9757919-2-9 }}{{Page needed|date=September 2010}}</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">{{cite journal | vauthors = Moore RA, Derry S | title = Systematic review and meta-analysis of randomised trials and cohort studies of mycophenolate mofetil in lupus nephritis | journal = Arthritis Research & Therapy | volume = 8 | issue = 6 | article-number = R182 | year = 2006 | pmid = 17163990 | pmc = 1794528 | doi = 10.1186/ar2093 | doi-access = free }}</ref> It is also used for retroperitoneal fibrosis along with a number of other medications.<ref>{{cite book|veditors=Harber M|title=Practical nephrology|date=2014|isbn=978-1-4471-5547-8|page=449|url=https://books.google.com/books?id=6GQgBAAAQBAJ&pg=PA449| vauthors = Harber M |publisher=Springer | access-date=23 September 2020|archive-date=29 April 2023|archive-url=https://web.archive.org/web/20230429051159/https://books.google.com/books?id=6GQgBAAAQBAJ&pg=PA449|url-status=live}}</ref> Specifically it has also been used for psoriasis not treatable by other methods.<ref name=silverman>{{cite journal | vauthors = Kitchin JE, Pomeranz MK, Pak G, Washenik K, Shupack JL | title = Rediscovering mycophenolic acid: a review of its mechanism, side effects, and potential uses | journal = Journal of the American Academy of Dermatology | volume = 37 | issue = 3 Pt 1 | pages = 445–9 | date = September 1997 | pmid = 9308561 | doi = 10.1016/S0190-9622(97)70147-6 | doi-access = free }}</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">{{cite journal | vauthors = D'Cruz DP, Khamashta MA, Hughes GR | title = Systemic lupus erythematosus | journal = Lancet | volume = 369 | issue = 9561 | pages = 587–96 | date = February 2007 | pmid = 17307106 | doi = 10.1016/S0140-6736(07)60279-7 | citeseerx = 10.1.1.1008.5428 | s2cid = 28468112 }}</ref> Further work addressing maintenance therapy demonstrated mycophenolate superior to cyclophosphamide, again in terms of response and side-effects.<ref name="DCruz"/><ref>{{cite journal | vauthors = Singh JA, Hossain A, Kotb A, Wells GA | title = Comparative effectiveness of immunosuppressive drugs and corticosteroids for lupus nephritis: a systematic review and network meta-analysis | journal = Systematic Reviews | volume = 5 | issue = 1 | article-number = 155 | date = September 2016 | pmid = 27619512 | pmc = 5020478 | doi = 10.1186/s13643-016-0328-z | doi-access = free }}</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">{{cite journal | vauthors = Walsh M, James M, Jayne D, Tonelli M, Manns BJ, Hemmelgarn BR | title = Mycophenolate mofetil for induction therapy of lupus nephritis: a systematic review and meta-analysis | journal = Clinical Journal of the American Society of Nephrology | volume = 2 | issue = 5 | pages = 968–75 | date = September 2007 | pmid = 17702723 | doi = 10.2215/CJN.01200307 | doi-access = free }}</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>{{cite journal | vauthors = Knight SR, Russell NK, Barcena L, Morris PJ | title = Mycophenolate mofetil decreases acute rejection and may improve graft survival in renal transplant recipients when compared with azathioprine: a systematic review | journal = Transplantation | volume = 87 | issue = 6 | pages = 785–94 | date = March 2009 | pmid = 19300178 | doi = 10.1097/TP.0b013e3181952623 | s2cid = 33596652 | doi-access = free }}</ref> Mycophenolic acid is 15 times more expensive than azathioprine.<ref>{{cite journal | vauthors = Remuzzi G, Lesti M, Gotti E, Ganeva M, Dimitrov BD, Ene-Iordache B, Gherardi G, Donati D, Salvadori M, Sandrini S, Valente U, Segoloni G, Mourad G, Federico S, Rigotti P, Sparacino V, Bosmans JL, Perico N, Ruggenenti P | title = Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial | journal = Lancet | volume = 364 | issue = 9433 | pages = 503–12 | year = 2004 | pmid = 15302193 | doi = 10.1016/S0140-6736(04)16808-6 | s2cid = 22033113 }}</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>{{cite web|url=http://reference.medscape.com/drug/cellcept-myfortic-mycophenolate-343209#4|title=Cellcept, Myfortic (mycophenolate) dosing, indications, interactions, adverse effects, and more|website=reference.medscape.com|access-date=9 November 2014|archive-date=30 April 2021|archive-url=https://web.archive.org/web/20210430035139/https://reference.medscape.com/drug/cellcept-myfortic-mycophenolate-343209#4|url-status=live}}</ref><ref>{{cite web|url=http://www.bnf.org/|title=Homepage - BNF Publications |website=www.bnf.org|access-date=9 November 2014|archive-date=27 April 2021|archive-url=https://web.archive.org/web/20210427213820/https://www.bnf.org/|url-status=live}}</ref>{{Nonspecific|date=March 2018}} Several cases of pure red cell aplasia (PRCA) have also been reported.<ref>{{cite web |url=https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm177397.htm |title=Cellcept (mycophenolate mofetil) August 2009 |date=14 August 2009 |access-date=21 August 2009 |publisher=U.S. Food and Drug Administration |archive-date=21 August 2009 |archive-url=https://web.archive.org/web/20090821063629/http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm177397.htm }}</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 investigating{{when|date=April 2020}} 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>{{cite web |url=https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm177397.htm |title=Cellcept (mycophenolate mofetil) August 2009 |date=14 August 2009 |access-date=21 August 2009 |publisher=U.S. Food and Drug Administration |archive-date=21 August 2009 |archive-url=https://web.archive.org/web/20090821063629/http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm177397.htm }}</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>{{cite web |url=http://www.newsinferno.com/archive/fda-issues-second-cellcept-warning/ |title=FDA Issues Second Cellcept Warning |publisher=newsinferno.com |date=18 May 2008 |access-date=26 October 2010 |archive-date=24 February 2013 |archive-url=https://web.archive.org/web/20130224081912/http://www.newsinferno.com/archive/fda-issues-second-cellcept-warning/ }}</ref><ref>{{cite web |url=https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm092157.htm |title=MedWatch Safety Alerts for Human Medical Products |publisher=fda.gov |date=May 2008 |access-date=26 October 2010 |archive-date=19 October 2010 |archive-url=https://web.archive.org/web/20101019142831/http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm092157.htm }}</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">{{cite book|title=Austria-Codex| veditors = Jasek W |publisher=Österreichischer Apothekerverlag|location=Vienna|year=2007|edition= 62nd|pages=1484–95|isbn=978-3-85200-181-4|language=de}}</ref><ref>Drugs.com: Mycophenolic acid {{Drugs.com|sfx|mycophenolic-acid-side-effects}}</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>{{cite book|title=Pharmacology North American Edition.|date=2014|publisher=Lippincott Williams & Wilkins|isbn=978-1-4511-9177-6|page=625}}</ref> IMPDH inhibition particularly affects lymphocytes since they rely almost exclusively on ''de novo'' purine synthesis.<ref>{{cite book| veditors = Parnham FP, Nijkamp MJ |title=Principles of immunopharmacology| url = https://archive.org/details/principlesimmuno00nijk_004 | url-access = limited |date=2005|publisher=Birkhèauser Verlag|location=Basel|isbn=978-3-7643-5804-4|page=[https://archive.org/details/principlesimmuno00nijk_004/page/n474 453]|edition=2nd rev. and extended}}</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>{{cite journal | vauthors = Fu R, Ceballos-Picot I, Torres RJ, Larovere LE, Yamada Y, Nguyen KV, Hegde M, Visser JE, Schretlen DJ, Nyhan WL, Puig JG, O'Neill PJ, Jinnah HA | title = Genotype-phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder | journal = Brain | volume = 137 | issue = Pt 5 | pages = 1282–303 | date = May 2014 | pmid = 23975452 | pmc = 3999711 | doi = 10.1093/brain/awt202 }}</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>{{cite journal| vauthors = Anderson HA, Bracewell JM, Fraser AR, Jones D, Robertson GW, Russell JD |title=5-Hydroxymaltol and mycophenolic acid, secondary metabolites from Penicillium echinulatum|journal=Transactions of the British Mycological Society|date=December 1988|volume=91|issue=4|pages=649–651|doi=10.1016/S0007-1536(88)80040-8}}</ref> Mycophenolate mofetil is metabolised in the liver to the active moiety mycophenolic acid. It reversibly inhibits inosine monophosphate dehydrogenase,<ref name="Fulton">{{cite journal | vauthors = Fulton B, Markham A | title = Mycophenolate mofetil. A review of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in renal transplantation | journal = Drugs | volume = 51 | issue = 2 | pages = 278–98 | date = February 1996 | pmid = 8808168 | doi = 10.2165/00003495-199651020-00007 | s2cid = 46954073 }}</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>{{cite journal | vauthors = Ransom JT | title = Mechanism of action of mycophenolate mofetil | journal = Therapeutic Drug Monitoring | volume = 17 | issue = 6 | pages = 681–4 | date = December 1995 | pmid = 8588241 | doi = 10.1097/00007691-199512000-00023 | s2cid = 6439393 }}</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>{{cite journal | vauthors = Dooley MA, Jayne D, Ginzler EM, Isenberg D, Olsen NJ, Wofsy D, Eitner F, Appel GB, Contreras G, Lisk L, Solomons N | title = Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis | journal = The New England Journal of Medicine | volume = 365 | issue = 20 | pages = 1886–95 | date = November 2011 | pmid = 22087680 | doi = 10.1056/NEJMoa1014460 | s2cid = 27689350 | url = https://cdr.lib.unc.edu/downloads/8623j6697 | doi-access = free | access-date = 25 November 2021 | archive-date = 8 March 2022 | archive-url = https://web.archive.org/web/20220308023022/https://cdr.lib.unc.edu/downloads/8623j6697 | url-status = live | hdl = 20.500.12648/8250 | hdl-access = free }}</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">{{cite journal | vauthors = Zhang W, Ding C, Zheng S | title = Enteric-coated mycophenolate sodium: an update | journal = International Journal of Clinical Practice. Supplement | volume = 68| issue = 181 | pages = 1–3 | date = April 2014 | pmid = 24673712 | doi = 10.1111/ijcp.12399 | s2cid = 2630344 | doi-access = free }}</ref>

==Chemistry== [[Image:Mycophenolate_mofetil_structure.png|300px|thumb|right|Mycophenolate mofetil, a prodrug form of mycophenolic acid used in medicine]] Mycophenolate mofetil is the morpholino{{zwnj}} ethyl ester of mycophenolic acid; the ester masks the carboxyl group.<ref name="pmid8918281">{{cite journal | vauthors = Lipsky JJ | title = Mycophenolate mofetil | journal = Lancet | volume = 348 | issue = 9038 | pages = 1357–9 | date = November 1996 | pmid = 8918281 | doi = 10.1016/S0140-6736(96)10310-X | s2cid = 36837474 }}</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''.{{cn|date=October 2023}}) 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>{{cite book| vauthors = Zhang L, Demain AL |title=Natural Products: Drug Discovery and Therapeutic Medicine|year=2005|publisher=Humana Press|location=Totowa, N.J.|isbn=978-1-59259-976-9|page=14|url=https://books.google.com/books?id=iP0i7x_38ZwC|access-date=16 August 2019|archive-date=29 April 2023|archive-url=https://web.archive.org/web/20230429051222/https://books.google.com/books?id=iP0i7x_38ZwC|url-status=live}}</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>{{cite journal | vauthors = Regueira TB, Kildegaard KR, Hansen BG, Mortensen UH, Hertweck C, Nielsen J | title = Molecular basis for mycophenolic acid biosynthesis in Penicillium brevicompactum | journal = Applied and Environmental Microbiology | volume = 77 | issue = 9 | pages = 3035–43 | date = May 2011 | pmid = 21398490 | pmc = 3126426 | doi = 10.1128/AEM.03015-10 | bibcode = 2011ApEnM..77.3035R }}</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>{{cite journal | vauthors = Bentley R | title = Mycophenolic Acid: a one hundred year odyssey from antibiotic to immunosuppressant | journal = Chemical Reviews | volume = 100 | issue = 10 | pages = 3801–26 | date = October 2000 | pmid = 11749328 | doi = 10.1021/cr990097b | bibcode = 2000ChRv..100.3801B }}</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, it could 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>{{cite journal| vauthors = Watts G |title=Anthony Clifford Allison|journal=The Lancet|year=2014|volume=383|issue=9925|page=1290|doi=10.1016/S0140-6736(14)60635-8|s2cid=54281245 |doi-access=free}}</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>{{cite journal | vauthors = Allison AC | title = Immunosuppressive drugs: the first 50 years and a glance forward | journal = Immunopharmacology | volume = 47 | issue = 2–3 | pages = 63–83 | date = May 2000 | pmid = 10878284 | doi = 10.1016/S0162-3109(00)00186-7 }}</ref><ref>{{cite journal | vauthors = Allison AC, Kowalski WJ, Muller CD, Eugui EM | title = Mechanisms of action of mycophenolic acid | journal = Annals of the New York Academy of Sciences | volume = 696 | issue = 1 | pages = 63–87 | date = November 1993 | pmid = 7906496 | doi = 10.1111/j.1749-6632.1993.tb17143.x | bibcode = 1993NYASA.696...63A | s2cid = 34520788 }}</ref> They synthesised a chemical variant for increased activity and reduced adverse effects.<ref>{{cite journal | vauthors = Nelson PH, Eugui E, Wang CC, Allison AC | title = Synthesis and immunosuppressive activity of some side-chain variants of mycophenolic acid | journal = Journal of Medicinal Chemistry | volume = 33 | issue = 2 | pages = 833–8 | date = February 1990 | pmid = 1967654 | doi = 10.1021/jm00164a057 }}</ref><ref>{{cite journal | vauthors = Eugui EM, Allison AC | title = Immunosuppressive activity of mycophenolate mofetil | journal = Annals of the New York Academy of Sciences | volume = 685 | issue = 1 | pages = 309–29 | date = June 1993 | pmid = 8363235 | doi = 10.1111/j.1749-6632.1993.tb35881.x | bibcode = 1993NYASA.685..309E | s2cid = 9028169 }}</ref><ref>{{cite journal | vauthors = Allison AC, Eugui EM | title = Purine metabolism and immunosuppressive effects of mycophenolate mofetil (MMF) | journal = Clinical Transplantation | volume = 10 | issue = 1 Pt 2 | pages = 77–84 | date = February 1996 | doi = 10.1111/j.1399-0012.1996.tb00651.x | pmid = 8680053 }}</ref><ref>{{cite journal | vauthors = Allison AC, Eugui EM | title = The design and development of an immunosuppressive drug, mycophenolate mofetil | journal = Springer Seminars in Immunopathology | volume = 14 | issue = 4 | pages = 353–80 | year = 1993 | pmid = 8322167 | doi = 10.1007/bf00192309 | s2cid = 26433174 }}</ref><ref>{{cite journal | vauthors = Allison AC, Eugui EM | title = Immunosuppressive and other effects of mycophenolic acid and an ester prodrug, mycophenolate mofetil | journal = Immunological Reviews | volume = 136 | issue = 1 | pages = 5–28 | date = December 1993 | pmid = 7907572 | doi = 10.1111/j.1600-065x.1993.tb00652.x | s2cid = 711727 }}</ref> They subsequently demonstrated that it was useful in organ transplantation in experimental rats.<ref>{{cite journal | vauthors = Bechstein WO, Suzuki Y, Kawamura T, Jaffee B, Allison A, Hullett DA, Sollinger HW | title = Low-dose combination therapy of DUP-785 and RS-61443 prolongs cardiac allograft survival in rats | journal = Transplant International | volume = 5 | issue = Suppl 1 | pages = S482-3 | year = 1992 | pmid = 14621853 | doi = 10.1111/tri.1992.5.s1.482 | s2cid = 222199749 }}</ref><ref>{{cite journal | vauthors = Kawamura T, Hullett DA, Suzuki Y, Bechstein WO, Allison AM, Sollinger HW | title = Enhancement of allograft survival by combination RS-61443 and DUP-785 therapy | journal = Transplantation | volume = 55 | issue = 4 | pages = 691–4; discussion 694–5 | date = April 1993 | pmid = 8475537 | doi = 10.1097/00007890-199304000-00001 | doi-access = free }}</ref> After successful clinical trials,<ref>{{cite journal | vauthors = Taylor DO, Ensley RD, Olsen SL, Dunn D, Renlund DG | title = Mycophenolate mofetil (RS-61443): preclinical, clinical, and three-year experience in heart transplantation | journal = The Journal of Heart and Lung Transplantation | volume = 13 | issue = 4 | pages = 571–82 | year = 1994 | pmid = 7947873 }}</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>{{cite web|title=Risk Evaluation and Mitigation Strategy (REMS) Under Review for Cellcept and Myfortic|url=https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm148735.htm|publisher=U.S. Food and Drug Administration|access-date=23 July 2014|archive-date=8 August 2014|archive-url=https://web.archive.org/web/20140808102218/http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm148735.htm}}</ref> and was sold under the brand name Cellcept.<ref>{{cite web| vauthors = Donlon DM |title=New Agent to Prevent Kidney Transplant Rejection Now Available |url=https://web.stanford.edu/dept/HPS/transplant/html/cell-cept.htm|publisher=Stanford University|access-date=23 July 2014|date=15 June 1995|archive-date=27 July 2014|archive-url=https://web.archive.org/web/20140727040934/http://web.stanford.edu/dept/HPS/transplant/html/cell-cept.htm|url-status=live}}</ref><ref>{{cite web|title=Cellcept registry data demonstrated superior long-term organ transplant outcomes|url=http://www.roche.com/investors/ir_update/inv-update-2004-05-17a.htm|website=Roche.com|publisher=F. Hoffmann-La Roche Ltd.|access-date=23 July 2014|archive-url=https://web.archive.org/web/20140726060253/http://www.roche.com/investors/ir_update/inv-update-2004-05-17a.htm|archive-date=26 July 2014}}</ref> It was approved for use in the European Union in February 1996.<ref name="CellCept EPAR">{{cite web | title=Cellcept EPAR | website=European Medicines Agency (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/cellcept | access-date=6 April 2020 | archive-date=6 April 2020 | archive-url=https://web.archive.org/web/20200406184051/https://www.ema.europa.eu/en/medicines/human/EPAR/cellcept | url-status=live }}</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>{{cite journal | vauthors = van Gelder T, Hesselink DA | title = Mycophenolate revisited | journal = Transplant International | volume = 28 | issue = 5 | pages = 508–15 | date = May 2015 | pmid = 25758949 | doi = 10.1111/tri.12554 | s2cid = 1673466 | doi-access = free }}</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>{{cite journal | vauthors = Mimouni D, Anhalt GJ, Cummins DL, Kouba DJ, Thorne JE, Nousari HC | title = Treatment of pemphigus vulgaris and pemphigus foliaceus with mycophenolate mofetil | journal = Archives of Dermatology | volume = 139 | issue = 6 | pages = 739–42 | date = June 2003 | pmid = 12810504 | doi = 10.1001/archderm.139.6.739 | doi-access = free }}</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.{{citation needed|date=September 2012}} A combination of mycophenolate and ribavirin has been found to stop infection by and replication of dengue virus ''in vitro''.<ref>{{cite journal | vauthors = Diamond MS, Zachariah M, Harris E | title = Mycophenolic acid inhibits dengue virus infection by preventing replication of viral RNA | journal = Virology | volume = 304 | issue = 2 | pages = 211–21 | date = December 2002 | pmid = 12504563 | doi = 10.1006/viro.2002.1685 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Takhampunya R, Ubol S, Houng HS, Cameron CE, Padmanabhan R | title = Inhibition of dengue virus replication by mycophenolic acid and ribavirin | journal = The Journal of General Virology | volume = 87 | issue = Pt 7 | pages = 1947–52 | date = July 2006 | pmid = 16760396 | doi = 10.1099/vir.0.81655-0 | doi-access = free }}</ref> It has also shown promising antiviral activity against MERS, especially in combination with interferon.<ref>{{cite journal | vauthors = Chan JF, Chan KH, Kao RY, To KK, Zheng BJ, Li CP, Li PT, Dai J, Mok FK, Chen H, Hayden FG, Yuen KY | title = Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus | journal = The Journal of Infection | volume = 67 | issue = 6 | pages = 606–16 | date = December 2013 | pmid = 24096239 | doi = 10.1016/j.jinf.2013.09.029 | pmc = 7112612 | doi-access = free }}</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>{{cite journal | vauthors = Xiao Y, Huang J, Luo H, Wang J | title = Mycophenolate mofetil for relapsing-remitting multiple sclerosis | journal = The Cochrane Database of Systematic Reviews | issue = 2 | article-number = CD010242 | date = February 2014 | volume = 2014 | pmid = 24505016 | doi = 10.1002/14651858.CD010242.pub2 | doi-access = free | pmc = 10875409 }}</ref>

==References== {{Reflist}}

{{DEFAULTSORT:Mycophenolic Acid}} Category:Carboxylic acids Category:Drugs developed by Genentech Category:Drugs developed by Hoffmann-La Roche Category:Immunosuppressants Category:Italian inventions Category:Drugs developed by Novartis Category:Isobenzofurans Category:Phenol ethers Category:Hydroxyarenes Category:Phthalides Category:South African inventions Category:Wikipedia medicine articles ready to translate

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