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Identification
Name Mycophenolate mofetil
Accession Number DB00688 (APRD01602)
Type small molecule
Groups approved
Description

Mycophenolate mofetil is the 2-morpholinoethyl ester of mycophenolic acid (MPA), an immunosuppressive agent, inosine monophosphate dehydrogenase (IMPDH) inhibitor.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Mycophenylate mofetil
Salts Not Available
Brand names
Name Company
CellCept
Munoloc
Brand mixtures Not Available
Categories
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Dermatologic Agents
  • Immunosuppressive Agents
CAS number 128794-94-5
Weight Average: 433.4947
Monoisotopic: 433.210052351
Chemical Formula C23H31NO7
InChI Key InChIKey=RTGDFNSFWBGLEC-SYZQJQIISA-N
InChI
InChI=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+
Plain Text
IUPAC Name
2-(morpholin-4-yl)ethyl (4E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methylhex-4-enoate
SMILES
COC1=C(C\C=C(/C)CCC(=O)OCCN2CCOCC2)C(O)=C2C(=O)OCC2=C1C
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Salicylates and Derivatives
  • Benzene and Derivatives
  • Benzyl Esters
  • Benzylacetates
  • Methoxyphenols
Substructures
  • Carboxylic Acids and Derivatives
  • Benzofurans
  • Hydroxy Compounds
  • Alkanes and Alkenes
  • Benzyl Alcohols and Derivatives
  • Acetates
  • Benzoates
  • Salicylates and Derivatives
  • Phenols and Derivatives
  • Lactones
  • Ethers
  • Benzene and Derivatives
  • Benzyl Esters
  • Benzylacetates
  • Methoxyphenols
  • Aliphatic and Aryl Amines
  • Heterocyclic compounds
  • Aromatic compounds
  • Anisoles
  • Morpholines
  • Benzoyl Derivatives
  • Phenyl Esters
Pharmacology
Indication For the prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac or hepatic transplants. Mycophenolate mofetil should be used concomitantly with cyclosporine and corticosteroids.
Pharmacodynamics Mycophenolate mofetil is a prodrug of mycophenolic acid, 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 action Mycophenolate mofetil is hydrolyzed to form mycophenolic acid (MPA), which is the active metabolite. MPA 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, MPA has potent cytostatic effects on lymphocytes. MPA inhibits proliferative responses of T- and B-lymphocytes to both mitogenic and allospecific stimulation. Addition of guanosine or deoxyguanosine reverses the cytostatic effects of MPA on lymphocytes. MPA also suppresses antibody formation by B-lymphocytes. MPA 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. Mycophenolate mofetil did not inhibit early events in the activation of human peripheral blood mononuclear cells, such as the production of interleukin-1 (IL-1) and interleukin-2 (IL-2), but did block the coupling of these events to DNA synthesis and proliferation.
Absorption Rapidly absorbed following oral administration. In 12 healthy volunteers, the mean absolute bioavailability of oral mycophenolate mofetil relative to intravenous mycophenolate mofetil (based on MPA AUC) was 94%. Food (27 g fat, 650 calories) has no effect on the extent of absorption (MPA AUC) of mycophenolate mofetil.
Volume of distribution
  • 3.6 ±1.5 L/kg [intravenous]
  • 4 ±1.2 L/kg [oral administration]
Protein binding MPA (the active metabolite), at clinically relevant concentrations, is over 98% bound to plasma albumin.
Metabolism Following oral and intravenous dosing, mycophenolate mofetil undergoes complete metabolism to MPA, the active metabolite. Metabolism to MPA occurs presystemically after oral dosing. MPA is metabolized principally by glucuronyl transferase to form the phenolic glucuronide of MPA (MPAG) which is not pharmacologically active. In vivo, MPAG is converted to MPA via enterohepatic recirculation. The following metabolites of the 2-hydroxyethyl-morpholino moiety are also recovered in the urine following oral administration of mycophenolate mofetil to healthy subjects: N-(2-carboxymethyl)-morpholine, N-(2-hydroxyethyl)-morpholine, and the N-oxide of N-(2-hydroxyethyl)-morpholine.
Route of elimination Negligible amount of drug is excreted as MPA (< 1% of dose) in the urine. Most (about 87%) of the administered dose is excreted in the urine as MPAG.
Half life The mean elimination half-life for mycophenolic acid (the active metabolite) ranges from 8-16 hours, while that of the MPAG metabolite ranges from 13-17 hours.
Clearance
  • 193 +/- 48 mL/min [following oral administration]
Toxicity Oral (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 Not Available
Pharmacoeconomics
Manufacturers
  • Roche palo alto llc
  • Accord healthcare inc usa
  • Apotex corp
  • Endo pharmaceuticals inc
  • Mylan pharmaceuticals inc
  • Roxane laboratories inc
  • Sandoz inc
  • Strides arcolab ltd
  • Teva pharmaceuticals usa
  • Zydus pharmaceuticals usa inc
  • Accord healthcare inc
  • Apotex inc
Packagers
Dosage forms
Form Route Strength
Capsule Oral
Powder, for solution Intravenous
Powder, for suspension Oral
Tablet Oral
Prices
Unit description Cost Unit
CellCept 200 mg/ml Suspension 175ml Bottle 875.84 USD bottle
Cellcept 500 mg vial 65.03 USD vial
Cellcept 500 mg tablet 10.43 USD tablet
Mycophenolate Mofetil 500 mg tablet 8.25 USD tablet
Mycophenolate 500 mg tablet 7.93 USD tablet
CellCept 250 mg capsule 5.21 USD capsule
Mycophenolate Mofetil 250 mg capsule 4.13 USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Country Patent Number Approved Expires (estimated)
United States 5688529 1994-11-18 2014-11-18
United States 5543408 1993-09-15 2013-09-15
Canada 2172506 2007-07-17 2014-09-27
Canada 1333285 1994-11-29 2011-11-29
Properties
State solid
Experimental Properties
Property Value Source
water solubility Slightly soluble (43 mg/mL at pH 7.4) Not Available
logP 2.5 Not Available
Predicted Properties
Property Value Source
water solubility 9.50e-02 g/l ALOGPS
logP 2.17 ALOGPS
logP 3.47 ChemAxon
logS -3.7 ALOGPS
pKa (strongest acidic) 9.76 ChemAxon
pKa (strongest basic) 6.19 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 6 ChemAxon
hydrogen donor count 1 ChemAxon
polar surface area 94.53 ChemAxon
rotatable bond count 10 ChemAxon
refractivity 117.1 ChemAxon
polarizability 45.55 ChemAxon
References
Synthesis Reference Not Available
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
Resource Link
KEGG Drug D00752 Link_out
KEGG Compound C07908 Link_out
PubChem Compound 5281078 Link_out
PubChem Substance 46505626 Link_out
ChemSpider 4444535 Link_out
Therapeutic Targets Database DNC000397 Link_out
PharmGKB PA450566 Link_out
Drug Product Database 2240347 Link_out
RxList http://www.rxlist.com/cgi/generic3/cellcept.htm Link_out
Drugs.com http://www.drugs.com/cdi/mycophenolate-mofetil.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Mycophenolate_mofetil Link_out
ATC Codes
  • L04AA06
AHFS Codes
  • 92:00.00
PDB Entries Not Available
FDA label show (200 KB)
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
Calcium Formation of non-absorbable complexes
Iron Oral iron decreases the absorption of mycophenolate-mofetil
Iron Dextran Oral iron decreases the absorption of mycophenolate-mofetil
Rifampin Rifampin may decrease the serum concentration of mycophenolate. Concomitant therapy should be avoided.
Rilonacept results in increased immunosuppressive effects; increases the risk of infection.
Tacrolimus Tacrolimus may increase the plasma concentration of Mycophenolic acid. Monitor and adjust the dose of Mycophenolate mofetil to the therapeutic range.
Trastuzumab Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Valganciclovir The excretion rates of Valganciclovir and/or Mycophenolate mofetil may decrease. Monitor for increased serum concentrations and toxicity of both agents.
Food Interactions
  • Do not take calcium, aluminium, magnesium or iron supplements within 2 hours of taking this medication.
  • Take on empty stomach: 1 hour before or 2 hours after meals.
Targets

1. Inosine-5'-monophosphate dehydrogenase 1

Pharmacological action: yes
Actions: inhibitor

Rate limiting enzyme in the de novo synthesis of guanine nucleotides and therefore is involved in the regulation of cell growth. It may also have a role in the development of malignancy and the growth progression of some tumors

Organism class: human
UniProt ID: P20839 Link_out
Gene: IMPDH1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Bremer S, Rootwelt H, Bergan S: Real-time PCR determination of IMPDH1 and IMPDH2 expression in blood cells. Clin Chem. 2007 Jun;53(6):1023-9. Epub 2007 Apr 26. Pubmed
  4. Wang J, Yang JW, Zeevi A, Webber SA, Girnita DM, Selby R, Fu J, Shah T, Pravica V, Hutchinson IV, Burckart GJ: IMPDH1 Gene Polymorphisms and Association With Acute Rejection in Renal Transplant Patients. Clin Pharmacol Ther. 2007 Sep 12;. Pubmed
  5. Sanquer S, Maison P, Tomkiewicz C, Macquin-Mavier I, Legendre C, Barouki R, Lang P: Expression of Inosine Monophosphate Dehydrogenase Type I and Type II After Mycophenolate Mofetil Treatment: A 2-year Follow-up in Kidney Transplantation. Clin Pharmacol Ther. 2007 Aug 22;. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Inosine-5'-monophosphate dehydrogenase 2

Pharmacological action: yes
Actions: inhibitor

Rate limiting enzyme in the de novo synthesis of guanine nucleotides and therefore is involved in the regulation of cell growth. It may also have a role in the development of malignancy and the growth progression of some tumors

Organism class: human
UniProt ID: P12268 Link_out
Gene: IMPDH2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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. Bremer S, Rootwelt H, Bergan S: Real-time PCR determination of IMPDH1 and IMPDH2 expression in blood cells. Clin Chem. 2007 Jun;53(6):1023-9. Epub 2007 Apr 26. Pubmed
  3. 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

Actions: substrate

UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX- alpha to form both the IX-alpha-C8 and IX-alpha-C12 monoconjugates and diconjugate

UniProt ID: P22309 Link_out
Gene: UGT1A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

2. UDP-glucuronosyltransferase 1-7

Actions: substrate
UniProt ID: Q9HAW7 Link_out

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

3. UDP-glucuronosyltransferase 1-6

Actions: substrate
UniProt ID: P19224 Link_out

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

4. UDP-glucuronosyltransferase 1-9

Actions: substrate

UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols

UniProt ID: O60656 Link_out
Gene: UGT1A9 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. 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

5. UDP-glucuronosyltransferase 2B7

Actions: substrate

Its unique specificity for 3,4-catechol estrogens and estriol suggests it may play an important role in regulating the level and activity of these potent and active estrogen metabolites

UniProt ID: P16662 Link_out
Gene: UGT2B7 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. 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

6. UDP-glucuronosyltransferase 1-8

Actions: substrate

UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds

UniProt ID: Q9HAW9 Link_out
Gene: UGT1A8 Link_out
Protein Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Thervet E, Anglicheau D, Legendre C: [Pharmacology of mycophenolate mofetil: recent data and clinical consequences]. Nephrologie. 2001;22(7):331-7. Pubmed

7. UDP-glucuronosyltransferase 1-10

Actions: substrate

UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds

UniProt ID: Q9HAW8 Link_out
Gene: UGT1A10 Link_out
Protein Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Thervet E, Anglicheau D, Legendre C: [Pharmacology of mycophenolate mofetil: recent data and clinical consequences]. Nephrologie. 2001;22(7):331-7. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19