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Identification
NameMycophenolic acid
Accession NumberDB01024  (APRD01603, EXPT02208)
TypeSmall Molecule
GroupsApproved
Description

Mycophenolic acid is an an immunosuppresant drug and potent anti-proliferative, and can be used in place of the older anti-proliferative azathioprine. It is usually used as part of triple therapy including a calcineurin inhibitor (ciclosporin or tacrolimus) and prednisolone. It is also useful in research for the selection of animal cells that express the E. coli gene coding for XGPRT (xanthine guanine phosphoribosyltransferase).

Structure
Thumb
Synonyms
SynonymLanguageCode
(e)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-5-phthalanyl)-4-methyl-4-hexenoic acidNot AvailableNot Available
Acide mycophenoliqueNot AvailableNot Available
Acido micofenolicoNot AvailableNot Available
Acidum mycophenolicumNot AvailableNot Available
Micofenolico acidoNot AvailableNot Available
Mycophenoic acidNot AvailableNot Available
MycophenolateNot AvailableNot Available
MycophenolsaeureNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
MelbexNot Available
MyforticNot Available
Brand mixturesNot Available
Categories
CAS number24280-93-1
WeightAverage: 320.3371
Monoisotopic: 320.125988372
Chemical FormulaC17H20O6
InChI KeyHPNSFSBZBAHARI-RUDMXATFSA-N
InChI
InChI=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+
IUPAC Name
(4E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methylhex-4-enoic acid
SMILES
COC1=C(C\C=C(/C)CCC(O)=O)C(O)=C2C(=O)OCC2=C1C
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassBenzofurans
SubclassBenzofuranones
Direct parentPhthalides
Alternative parentsHydroxybenzoic Acid Derivatives; Methoxyphenols and Derivatives; Anisoles; Para Cresols; Branched Fatty Acids; Toluenes; Alkyl Aryl Ethers; Heterocyclic Fatty Acids; Unsaturated Fatty Acids; Dicarboxylic Acids and Derivatives; Polyols; Carboxylic Acid Esters; Carboxylic Acids; Dialkyl Ethers; Polyamines; Enolates; Enols
Substituentsanisole; phenol ether; p-cresol; phenol derivative; alkyl aryl ether; toluene; benzene; dicarboxylic acid derivative; carboxylic acid ester; polyol; ether; dialkyl ether; carboxylic acid; enol; carboxylic acid derivative; polyamine; enolate
Classification descriptionThis compound belongs to the phthalides. These are compounds containing a 3-hydrocarbylidene-2-benzofuran-1(3H)-one moiety,.
Pharmacology
IndicationFor the prophylaxis of organ rejection in patients receiving allogeneic renal transplants, administered in combination with cyclosporine and corticosteroids.
PharmacodynamicsMycophenolic acid is an antibiotic substance derived from Penicillium stoloniferum. It blocks de novo biosynthesis of purine nucleotides by inhibition of the enzyme inosine monophosphate dehydrogenase. Mycophenolic acid is important because of its selective effects on the immune system. It prevents the proliferation of T-cells, lymphocytes, and the formation of antibodies from B-cells. It also may inhibit recruitment of leukocytes to inflammatory sites.
Mechanism of actionMycophenolic acid is a potent, selective, uncompetitive, and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. Because T- and B-lymphocytes are critically dependent for their proliferation on de novo synthesis of purines, whereas other cell types can utilize salvage pathways, mycophenolic acid has potent cytostatic effects on lymphocytes. Mycophenolic acid inhibits proliferative responses of T- and B-lymphocytes to both mitogenic and allospecific stimulation. Addition of guanosine or deoxyguanosine reverses the cytostatic effects of mycophenolic acid on lymphocytes. Mycophenolic acid also suppresses antibody formation by B-lymphocytes. Mycophenolic acid prevents the glycosylation of lymphocyte and monocyte glycoproteins that are involved in intercellular adhesion to endothelial cells and may inhibit recruitment of leukocytes into sites of inflammation and graft rejection.
AbsorptionBioavailability following oral administration of Myfortic delayed-release tablet ranges from 70-95%
Volume of distribution
  • 54 ± 25 L
Protein binding>98%
Metabolism

Mycophenolic acid is metabolized mainly by glucuronyl transferase to glucuronidated metabolites, predominantly the phenolic glucuronide, mycophenolic acid glucuronide (MPAG). MPAG does not manifest pharmacological activity. The acyl glucuronide minor metabolite has pharmacological activity similar to mycophenolic acid. The AUC ratio of Mycophenolic acid:MPAG:acyl glucuronide is approximately 1:24:0.28 at steady state.

SubstrateEnzymesProduct
Mycophenolic acid
Mycophenolic acid-acyl glucuronideDetails
Mycophenolic acid
6-O-desmethyl-mycophenolic acidDetails
Mycophenolic acid
Mycophenolic acid-7-O-glucuornideDetails
Route of eliminationNot Available
Half lifeThe mean elimination half-life for mycophenolic acid ranges from 8-16 hours, while that of the MPAG metabolite ranges from 13-17 hours.
Clearance
  • 140 +/- 30 mL/min [Stable renal transplant patients]
ToxicityOral (LD50): Acute: 352 mg/kg [Rat], 1000 mg/kg [Mouse], and >6000 mg/kg [Rabbit]. Possible signs and symptoms of acute overdose could include the following: hematological abnormalities such as leukopenia and neutropenia, and gastrointestinal symptoms such as abdominal pain, diarrhea, nausea and vomiting, and dyspepsia.
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Mycophenolic Acid Metabolism PathwayDrug metabolismSMP00652
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9409
Blood Brain Barrier + 0.5826
Caco-2 permeable - 0.5583
P-glycoprotein substrate Substrate 0.8058
P-glycoprotein inhibitor I Non-inhibitor 0.7888
P-glycoprotein inhibitor II Inhibitor 0.545
Renal organic cation transporter Non-inhibitor 0.8199
CYP450 2C9 substrate Non-substrate 0.8305
CYP450 2D6 substrate Non-substrate 0.8575
CYP450 3A4 substrate Substrate 0.6934
CYP450 1A2 substrate Inhibitor 0.9107
CYP450 2C9 substrate Non-inhibitor 0.907
CYP450 2D6 substrate Non-inhibitor 0.9232
CYP450 2C19 substrate Non-inhibitor 0.9025
CYP450 3A4 substrate Inhibitor 0.796
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.7237
Ames test AMES toxic 0.9107
Carcinogenicity Non-carcinogens 0.9619
Biodegradation Ready biodegradable 0.5888
Rat acute toxicity 2.9907 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.753
hERG inhibition (predictor II) Non-inhibitor 0.6329
Pharmacoeconomics
Manufacturers
  • Novartis pharmaceuticals corp
Packagers
Dosage forms
FormRouteStrength
Tablet, coatedOral
Prices
Unit descriptionCostUnit
Myfortic 360 mg Enteric Coated Tabs8.0USDtab
Myfortic 360 mg tablet7.69USDtablet
Myfortic 180 mg tablet3.85USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States60253911997-04-102017-04-10
Canada22509062006-10-032017-04-10
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point141 °CPhysProp
water solubilityInsolubleNot Available
logP2.8Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0355ALOGPS
logP2.36ALOGPS
logP3.53ChemAxon
logS-4ALOGPS
pKa (Strongest Acidic)3.57ChemAxon
pKa (Strongest Basic)-4.1ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area93.06 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity85.23 m3·mol-1ChemAxon
Polarizability32.95 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Bernard J. Abbott, John G. Whitney, “Method of preparing mycophenolic acid glucoside.” U.S. Patent US4234684, issued January, 1976.

US4234684
General Reference
  1. Woodroffe R, Yao GL, Meads C, Bayliss S, Ready A, Raftery J, Taylor RS: Clinical and cost-effectiveness of newer immunosuppressive regimens in renal transplantation: a systematic review and modelling study. Health Technol Assess. 2005 May;9(21):1-179, iii-iv. Pubmed
External Links
ResourceLink
PubChem Compound446541
PubChem Substance46504559
ChemSpider393865
BindingDB19264
ChEBI168396
ChEMBLCHEMBL866
Therapeutic Targets DatabaseDAP000784
PharmGKBPA164748728
HETMOA
Drug Product Database2264560
Drugs.comhttp://www.drugs.com/cdi/mycophenolic-acid-delayed-release-tablets.html
WikipediaMycophenolic_acid
ATC CodesNot Available
AHFS Codes
  • 92:00.00
PDB Entries
FDA labelNot Available
MSDSshow(74 KB)
Interactions
Drug Interactions
Drug
TrastuzumabTrastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
ValganciclovirThe excretion rates of Valganciclovir and/or Mycophenolic acid may decrease. Monitor for increased serum concentrations and toxicity of both agents.
Food InteractionsNot Available

Targets

1. Inosine-5'-monophosphate dehydrogenase 1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Inosine-5'-monophosphate dehydrogenase 1 P20839 Details

References:

  1. Dzidic A, Prgomet C, Mohr A, Meyer K, Bauer J, Meyer HH, Pfaffl MW: Effects of mycophenolic acid on inosine monophosphate dehydrogenase I and II mRNA expression in white blood cells and various tissues in sheep. J Vet Med A Physiol Pathol Clin Med. 2006 May;53(4):163-9. Pubmed

2. Inosine-5'-monophosphate dehydrogenase 2

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Inosine-5'-monophosphate dehydrogenase 2 P12268 Details

References:

  1. Vannozzi F, Filipponi F, Di Paolo A, Danesi R, Urbani L, Bocci G, Catalano G, De Simone P, Mosca F, Del Tacca M: An exploratory study on pharmacogenetics of inosine-monophosphate dehydrogenase II in peripheral mononuclear cells from liver-transplant recipients. Transplant Proc. 2004 Nov;36(9):2787-90. Pubmed
  2. Wang J, Zeevi A, Webber S, Girnita DM, Addonizio L, Selby R, Hutchinson IV, Burckart GJ: A novel variant L263F in human inosine 5’-monophosphate dehydrogenase 2 is associated with diminished enzyme activity. Pharmacogenet Genomics. 2007 Apr;17(4):283-90. Pubmed
  3. Penuelas S, Noe V, Morales R, Ciudad CJ: Sensitization of human erythroleukemia K562 cells resistant to methotrexate by inhibiting IMPDH. Med Sci Monit. 2005 Jan;11(1):BR6-12. Pubmed
  4. Yam P, Jensen M, Akkina R, Anderson J, Villacres MC, Wu J, Zaia JA, Yee JK: Ex vivo selection and expansion of cells based on expression of a mutated inosine monophosphate dehydrogenase 2 after HIV vector transduction: effects on lymphocytes, monocytes, and CD34+ stem cells. Mol Ther. 2006 Aug;14(2):236-44. Epub 2006 May 2. Pubmed
  5. Dzidic A, Prgomet C, Mohr A, Meyer K, Bauer J, Meyer HH, Pfaffl MW: Effects of mycophenolic acid on inosine monophosphate dehydrogenase I and II mRNA expression in white blood cells and various tissues in sheep. J Vet Med A Physiol Pathol Clin Med. 2006 May;53(4):163-9. Pubmed
  6. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. Pubmed
  7. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

Enzymes

1. UDP-glucuronosyltransferase 1-1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 1-1 P22309 Details

References:

  1. Dostalek M, Court MH, Hazarika S, Akhlaghi F: Diabetes mellitus reduces activity of human UDP-glucuronosyltransferase 2B7 in liver and kidney leading to decreased formation of mycophenolic acid acyl-glucuronide metabolite. Drug Metab Dispos. 2011 Mar;39(3):448-55. Epub 2010 Dec 1. Pubmed
  2. Miles KK, Kessler FK, Smith PC, Ritter JK: Characterization of rat intestinal microsomal UDP-glucuronosyltransferase activity toward mycophenolic acid. Drug Metab Dispos. 2006 Sep;34(9):1632-9. Epub 2006 Jun 21. Pubmed

2. UDP-glucuronosyltransferase 1-9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 1-9 O60656 Details

References:

  1. Dostalek M, Court MH, Hazarika S, Akhlaghi F: Diabetes mellitus reduces activity of human UDP-glucuronosyltransferase 2B7 in liver and kidney leading to decreased formation of mycophenolic acid acyl-glucuronide metabolite. Drug Metab Dispos. 2011 Mar;39(3):448-55. Epub 2010 Dec 1. Pubmed
  2. Picard N, Ratanasavanh D, Premaud A, Le Meur Y, Marquet P: Identification of the UDP-glucuronosyltransferase isoforms involved in mycophenolic acid phase II metabolism. Drug Metab Dispos. 2005 Jan;33(1):139-46. Epub 2004 Oct 6. Pubmed

3. UDP-glucuronosyltransferase 2B7

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 2B7 P16662 Details

References:

  1. Dostalek M, Court MH, Hazarika S, Akhlaghi F: Diabetes mellitus reduces activity of human UDP-glucuronosyltransferase 2B7 in liver and kidney leading to decreased formation of mycophenolic acid acyl-glucuronide metabolite. Drug Metab Dispos. 2011 Mar;39(3):448-55. Epub 2010 Dec 1. Pubmed
  2. Picard N, Ratanasavanh D, Premaud A, Le Meur Y, Marquet P: Identification of the UDP-glucuronosyltransferase isoforms involved in mycophenolic acid phase II metabolism. Drug Metab Dispos. 2005 Jan;33(1):139-46. Epub 2004 Oct 6. Pubmed

4. UDP-glucuronosyltransferase 1-7

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 1-7 Q9HAW7 Details

References:

  1. Miles KK, Kessler FK, Smith PC, Ritter JK: Characterization of rat intestinal microsomal UDP-glucuronosyltransferase activity toward mycophenolic acid. Drug Metab Dispos. 2006 Sep;34(9):1632-9. Epub 2006 Jun 21. Pubmed

5. UDP-glucuronosyltransferase 1-6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 1-6 P19224 Details

References:

  1. Miles KK, Kessler FK, Smith PC, Ritter JK: Characterization of rat intestinal microsomal UDP-glucuronosyltransferase activity toward mycophenolic acid. Drug Metab Dispos. 2006 Sep;34(9):1632-9. Epub 2006 Jun 21. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:13