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Identification
Name Indomethacin
Accession Number DB00328 (APRD00109)
Type small molecule
Groups approved
Description

Indomethacin is a non-steroidal antiinflammatory agent (NSAIA) with antiinflammatory, analgesic and antipyretic activity. Its pharmacological effect is thought to be mediated through inhibition of the enzyme cyclooxygenase (COX), the enzyme responsible for catalyzes the rate-limiting step in prostaglandin synthesis via the arachidonic acid pathway.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • IMN
  • Indometacine
  • Indometacyna
  • indomethacin
  • Indomethacine
  • Indomethacinum
  • Indomethancin
  • Indomethazine
  • Indomethine
  • Indometicina
Brand names
  • Amuno
  • Apo-Indomethacin
  • Argun
  • Arthrexin
  • Artracin
  • Artrinovo
  • Artrivia
  • Bonidin
  • Bonidon
  • Bonidon Gel
  • Catlep
  • Chibro-Amuno
  • Chrono-Indicid
  • Chrono-Indocid
  • Confortid
  • Dolcidium
  • Dolcidium Pl
  • Dolovin
  • Durametacin
  • Elmetacin
  • Flexin Continus
  • Hicin
  • Idomethine
  • Imbrilon
  • Inacid
  • Indacin
  • Indaflex
  • Indameth
  • Indmethacine
  • Indo-Lemmon
  • Indo-Phlogont
  • Indo-Rectolmin
  • Indo-Spray
  • Indo-Tablinen
  • Indocid
  • Indocid Pda
  • Indocid Sr
  • Indocin
  • Indocin I.V
  • Indocin I.V.
  • Indocin Sr
  • Indolar Sr
  • Indomecol
  • Indomed
  • Indomee
  • Indomethegan
  • Indomo
  • Indomod
  • Indoptic
  • Indoptol
  • Indorektal
  • Indoxen
  • Inflazon
  • Infrocin
  • Inteban Sp
  • Lausit
  • Liometacen
  • Metacen
  • Metartril
  • Methazine
  • Metindol
  • Miametan
  • Mikametan
  • Mobilan
  • Novo-Methacin
  • Novomethacin
  • Nu-Indo
  • Reumacide
  • Rhemacin La
  • Rheumacin La
  • Sadoreum
  • Tannex
  • Vonum
Brand name mixtures Not Available
Categories
  • Anti-inflammatory Agents
  • Cyclooxygenase Inhibitors
  • Tocolytic Agents
  • Cardiovascular Agents
  • Nonsteroidal Anti-inflammatory Agents (NSAIAs)
  • Gout Suppressants
CAS number 53-86-1
Weight Average: 357.788
Monoisotopic: 357.076785712
Chemical Formula C19H16ClNO4
InChI Key InChIKey=CGIGDMFJXJATDK-UHFFFAOYSA-N
InChI
InChI=1S/C19H16ClNO4/c1-11-15(10-18(22)23)16-9-14(25-2)7-8-17(16)21(11)19(24)12-3-5-13(20)6-4-12/h3-9H,10H2,1-2H3,(H,22,23)
Plain Text
IUPAC Name
2-{1-[(4-chlorophenyl)carbonyl]-5-methoxy-2-methyl-1H-indol-3-yl}acetic acid
SMILES
COC1=CC2=C(C=C1)N(C(=O)C1=CC=C(Cl)C=C1)C(C)=C2CC(O)=O
Plain Text
Mass Spec show (7.7 KB)
Taxonomy
Kingdom Organic
Classes
  • Indoles and Indole Derivatives
Substructures
  • Hydroxy Compounds
  • Acetates
  • Indoles and Indole Derivatives
  • Phenols and Derivatives
  • Amino Ketones
  • Carboxylic Acids and Derivatives
  • Pyrroles
  • Ethers
  • Benzene and Derivatives
  • Aryl Halides
  • Halobenzenes
  • Heterocyclic compounds
  • Aromatic compounds
  • Anisoles
  • Carboxamides and Derivatives
  • Imines
  • Benzoyl Derivatives
  • Phenyl Esters
  • Benzamides
Pharmacology
Indication For moderate to severe rheumatoid arthritis including acute flares of chronic disease, ankylosing spondylitis, osteoarthritis, acute painful shoulder (bursitis and/or tendinitis) and acute gouty arthritis.
Pharmacodynamics Indomethacin, a NSAIA, with analgesic and antipyretic properties exerts its pharmacological effects by inhibiting the synthesis of prostaglandins involved in pain, fever, and inflammation. Indomethacin inhibits the catalytic activity of the COX enzymes, the enzymes responsible for catalyzing the rate-limiting step in prostaglandin synthesis via the arachidonic acid pathway. Indomethacin is known to inhibit two well-characterized isoforms of COX, COX-1 and COX-2, with greater selectivity for COX-1. COX-1 is a constitutively expressed enzyme that is involved in gastric mucosal protection, platelet and kidney function. It catalyzes the conversion of arachidonic acid to prostaglandin (PG) G2 and PGG2 to PGH2. COX-1 is involved in the synthesis pathways of PGE2, PGD2, PDF2a, PGI2 (also known as prostacyclin) and thromboxane A2 (TXA2). COX-2 is constitutively expressed and highly inducible by inflammatory stimuli. It is found in the central nervous system, kidneys, uterus and other organs. It also catalyzes the conversion of arachidonic acid to PGG2 and PGG2 to PGH2. In the COX-2-mediated pathway, PGH2 is subsequently converted to PGE2 and PGI2 (also known as prostacyclin). PGE2 is involved in mediating inflammation, pain and fever. Decreasing levels of PGE2 leads to decreased inflammation.
Mechanism of action Indomethacin is a prostaglandin G/H synthase (also known as cyclooxygenase or COX) inhibitor that acts on both prostaglandin G/H synthase 1 and 2 (COX-1 and -2). Prostaglandin G/H synthase catalyzes the conversion of arachidonic acid to a number of prostaglandins involved in fever, pain, swelling, inflammation, and platelet aggregation. Indomethacin antagonizes COX by binding to the upper portion of the active site, preventing its substrate, arachidonic acid, from entering the active site. Indomethacin, unlike other NSAIDs, also inhibits phospholipase A2, the enzyme responsible for releasing arachidonic acid from phospholipids. Indomethacin is more selective for COX-1 than COX-2, which accounts for its increased adverse gastric effects relative to other NSAIDs. COX-1 is required for maintaining the protective gastric mucosal layer. The analgesic, antipyretic and anti-inflammatory effects of indomethacin occur as a result of decreased prostaglandin synthesis. Its antipyretic effects may be due to action on the hypothalamus, resulting in an increased peripheral blood flow, vasodilation, and subsequent heat dissipation.
Absorption Bioavailability is approximately 100% following oral administration and 80–90% following rectal administration.
Volume of distribution Not Available
Protein binding 97%
Metabolism

Hepatic.

Enzyme Metabolite Reaction Km Vmax
Liver carboxylesterase 1 N-Deschlorobenzoyl indomethacin
Cytochrome P450 2C9 O-Desmethylindomethacin O-demethylation 9.9 5.93
Cytochrome P450 2C19 O-Desmethylindomethacin
UDP-glucuronosyltransferase 1-1 Indomethacin acyl glucuronide
Route of elimination Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion.
Half life 4.5 hours
Clearance Not Available
Toxicity The following symptoms may be observed following overdosage: nausea, vomiting, intense headache, dizziness, mental confusion, disorientation, or lethargy. There have been reports of paresthesias, numbness, and convulsions. The oral LD50 of indomethacin in mice and rats (based on 14 day mortality response) was 50 and 12 mg/kg, respectively.
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00104 Indomethacin Pathway SMP00104
Pharmacoeconomics
Manufacturers
  • Iroko pharmaceuticals llc
  • Sandoz inc
  • Able laboratories inc
  • Avanthi inc
  • Inwood laboratories inc sub forest laboratories inc
  • Teva pharmaceuticals usa inc
  • Duramed pharmaceuticals inc sub barr laboratories inc
  • Halsey drug co inc
  • Heritage pharmaceuticals inc
  • Ivax pharmaceuticals inc sub teva pharmaceuticals usa
  • Mutual pharmaceutical co inc
  • Mylan pharmaceuticals inc
  • Parke davis div warner lambert co
  • Pioneer pharmaceuticals inc
  • Pliva inc
  • Roxane laboratories inc
  • Superpharm corp
  • Vintage pharmaceuticals llc
  • Watson laboratories inc
  • App pharmaceuticals llc
  • G and w laboratories inc
  • Lundbeck inc
  • Bedford laboratories div ben venue laboratories inc
Packagers
Dosage forms
Form Route Strength
Capsule Oral 25 mg
Capsule Oral 50 mg
Capsule, extended release Oral 75 mg
Injection Intravenous 1 mg
Suppository Rectal 100 mg
Suppository Rectal 50 mg
Suspension Oral 25 mg/5 ml
Prices
Unit description Cost Unit
Indocin i.v. 1 mg vial 642.6 USD vial
Indomethacin 1 mg vial 600.0 USD vial
Indocin 50 mg suppository 9.56 USD suppository
Indomethacin CR 75 mg capsule 3.12 USD capsule
Indocin sr 75 mg capsule 2.92 USD capsule
Indomethacin powder 2.57 USD g
Ratio-Indomethacin 100 mg Suppository 0.93 USD suppository
Sandoz Indomethacin 100 mg Suppository 0.93 USD suppository
Sandoz Indomethacin 50 mg Suppository 0.93 USD suppository
Indomethacin 50 mg capsule 0.65 USD capsule
Indomethacin 25 mg capsule 0.44 USD capsule
Apo-Indomethacin 50 mg Capsule 0.16 USD capsule
Novo-Methacin 50 mg Capsule 0.16 USD capsule
Nu-Indo 50 mg Capsule 0.16 USD capsule
Apo-Indomethacin 25 mg Capsule 0.09 USD capsule
Novo-Methacin 25 mg Capsule 0.09 USD capsule
Nu-Indo 25 mg Capsule 0.09 USD capsule
Patents Not Available
Properties
State solid
Melting point 158 oC
Experimental Properties
Property Value Source
water solubility 0.937 mg/L PhysProp
logP 3.4 PhysProp
logS -4.62 [ADME Research, USCD] PhysProp
Caco2 permeability -4.69 [ADME Research, USCD] BiGG
pKa 4.5 Various sources
Predicted Properties
Property Value Source
water solubility 2.40e-03 g/l ALOGPS
logP 4.25 ALOGPS
logP 3.53 ChemAxon Molconvert
logS -5.17 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 4 ChemAxon Molconvert
hydrogen donor count 1 ChemAxon Molconvert
polar surface area 68.53 ChemAxon Molconvert
rotatable bond count 4 ChemAxon Molconvert
refractivity 94.81 ChemAxon Molconvert
polarizability 36.64 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Akbarpour F, Afrasiabi A, Vaziri ND: Severe hyperkalemia caused by indomethacin and potassium supplementation. South Med J. 1985 Jun;78(6):756-7. Pubmed
  2. HART FD, BOARDMAN PL: INDOMETHACIN: A NEW NON-STEROID ANTI-INFLAMMATORY AGENT. Br Med J. 1963 Oct 19;2(5363):965-70. Pubmed
  3. Lum GM, Aisenbrey GA, Dunn MJ, Berl T, Schrier RW, McDonald KM: In vivo effect of indomethacin to potentiate the renal medullary cyclic AMP response to vasopressin. J Clin Invest. 1977 Jan;59(1):8-13. Pubmed
  4. Phelan KM, Mosholder AD, Lu S: Lithium interaction with the cyclooxygenase 2 inhibitors rofecoxib and celecoxib and other nonsteroidal anti-inflammatory drugs. J Clin Psychiatry. 2003 Nov;64(11):1328-34. Pubmed
  5. Ragheb M: The clinical significance of lithium-nonsteroidal anti-inflammatory drug interactions. J Clin Psychopharmacol. 1990 Oct;10(5):350-4. Pubmed
External Links
Resource Link
KEGG Drug D00141 Link_out
KEGG Compound C01926 Link_out
PubChem Compound 3715 Link_out
PubChem Substance 46508291 Link_out
ChemSpider 3584 Link_out
BindingDB 17638 Link_out
ChEBI 5918 Link_out
ChEMBL 5918 Link_out
Therapeutic Targets Database DAP000617 Link_out
PharmGKB PA449982 Link_out
Drug Product Database 2143372 Link_out
RxList http://www.rxlist.com/cgi/generic/indometh.htm Link_out
Drugs.com http://www.drugs.com/cdi/indomethacin.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Indomethacin Link_out
ATC Codes
  • M01AB01
  • C01EB03
AHFS Codes
  • 28:08.04.92
PDB Entries Not Available
FDA label show (56.2 KB)
MSDS show (73.2 KB)
Interactions
Drug Interactions Not Available
Food Interactions
  • Avoid alcohol.
  • Take with food or antacids to reduce irritation.
Targets

1. Prostaglandin G/H synthase 1

Pharmacological action: unknown
Actions: inhibitor

May play an important role in regulating or promoting cell proliferation in some normal and neoplastically transformed cells

Organism class: human
UniProt ID: P23219 Link_out
Gene: PTGS1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Bobadilla L RA, Perez-Alvarez V, Bracho Valdes I, Lopez-Sanchez P: Effect of pregnancy on the roles of nitric oxide and prostaglandins in 5-hydroxytryptamine-induced contractions in rat isolated thoracic and abdominal aorta. Clin Exp Pharmacol Physiol. 2005 Mar;32(3):202-9. Pubmed
  2. Fornai M, Blandizzi C, Colucci R, Antonioli L, Bernardini N, Segnani C, Baragatti B, Barogi S, Berti P, Spisni R, Del Tacca M: Role of cyclooxygenases 1 and 2 in the modulation of neuromuscular functions in the distal colon of humans and mice. Gut. 2005 May;54(5):608-16. Pubmed
  3. Higuchi K, Tominaga K, Watanabe T, Uno H, Shiba M, Sasaki E, Tanigawa T, Takashima T, Hamaguchi M, Oshitani N, Matsumoto T, Iwanaga Y, Fukuda T, Fujiwara Y, Arakawa T: Indomethacin, but not Helicobacter pylori, inhibits adaptive relaxation in isolated guinea-pig stomach. Drugs Exp Clin Res. 2004;30(5-6):235-41. Pubmed
  4. Kundu N, Walser TC, Ma X, Fulton AM: Cyclooxygenase inhibitors modulate NK activities that control metastatic disease. Cancer Immunol Immunother. 2005 Oct;54(10):981-7. Epub 2005 May 13. Pubmed
  5. Moth CW, Prusakiewicz JJ, Marnett LJ, Lybrand TP: Stereoselective binding of indomethacin ethanolamide derivatives to cyclooxygenase-1. J Med Chem. 2005 May 19;48(10):3613-20. Pubmed

2. Prostaglandin G/H synthase 2

Pharmacological action: yes
Actions: inhibitor

May have a role as a major mediator of inflammation and/or a role for prostanoid signaling in activity-dependent plasticity

Organism class: human
UniProt ID: P35354 Link_out
Gene: PTGS2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Armstrong PJ, Franklin DP, Carey DJ, Elmore JR: Suppression of experimental aortic aneurysms: comparison of inducible nitric oxide synthase and cyclooxygenase inhibitors. Ann Vasc Surg. 2005 Mar;19(2):248-57. Pubmed
  2. Jerde TJ, Calamon-Dixon JL, Bjorling DE, Nakada SY: Celecoxib inhibits ureteral contractility and prostanoid release. Urology. 2005 Jan;65(1):185-90. Pubmed
  3. Pilane CM, Labelle EF: Nitric oxide stimulated vascular smooth muscle cells undergo apoptosis induced in part by arachidonic acid derived eicosanoids. J Cell Physiol. 2005 Aug;204(2):423-7. Pubmed
  4. Yokota A, Taniguchi M, Takahira Y, Tanaka A, Takeuchi K: Rofecoxib produces intestinal but not gastric damage in the presence of a low dose of indomethacin in rats. J Pharmacol Exp Ther. 2005 Jul;314(1):302-9. Epub 2005 Apr 14. Pubmed
  5. Zhang GS, Fu YB, Xia M: [Proliferation inhibition effect of indomethacin on CML cells associated with down-regulation of phosphorylated STAT1/STAT5 and inhibition of COX-2 expression.] Zhonghua Xue Ye Xue Za Zhi. 2004 Dec;25(12):732-5. Pubmed

3. Phospholipase A2, membrane associated

Pharmacological action: yes
Actions: inhibitor

Thought to participate in the regulation of the phospholipid metabolism in biomembranes including eicosanoid biosynthesis. Catalyzes the calcium-dependent hydrolysis of the 2- acyl groups in 3-sn-phosphoglycerides

Organism class: human
UniProt ID: P14555 Link_out
Gene: PLA2G2A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Geisslinger, G., & Lötsch, J. (2004). Non-steroidal anti-inflammatory drugs. In S. Offermanns, & W. Rosenthal (Eds.). Encyclopedic reference of molecular pharmacology (pp. 667-671). Berlin, Germany: Springer.

4. Prostaglandin reductase 2

Pharmacological action: unknown
Actions: inhibitor

Functions as 15-oxo-prostaglandin 13-reductase and acts on 15-keto-PGE1, 15-keto-PGE2, 15-keto-PGE1-alpha and 15-keto- PGE2-alpha with highest activity towards 15-keto-PGE2. Overexpression represses transcriptional activity of PPARG and inhibits adipocyte differentiation (By similarity)

Organism class: human
UniProt ID: Q8N8N7 Link_out
Gene: PTGR2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Wu YH, Ko TP, Guo RT, Hu SM, Chuang LM, Wang AH: Structural basis for catalytic and inhibitory mechanisms of human prostaglandin reductase PTGR2. Structure. 2008 Nov 12;16(11):1714-23. Pubmed

5. Peroxisome proliferator-activated receptor gamma

Pharmacological action: unknown
Actions: activator

Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the receptor binds to a promoter element in the gene for acyl-CoA oxidase and activates its transcription. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis

Organism class: human
UniProt ID: P37231 Link_out
Gene: PPARG Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Cho MC, Lee HS, Kim JH, Choe YK, Hong JT, Paik SG, Yoon DY: A simple ELISA for screening ligands of peroxisome proliferator-activated receptor-gamma. J Biochem Mol Biol. 2003 Mar 31;36(2):207-13. Pubmed

6. Lactoylglutathione lyase

Pharmacological action: unknown
Actions: inhibitor

Catalyzes the conversion of hemimercaptal, formed from methylglyoxal and glutathione, to S-lactoylglutathione

Organism class: human
UniProt ID: Q04760 Link_out
Gene: GLO1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Sato S, Kwon Y, Kamisuki S, Srivastava N, Mao Q, Kawazoe Y, Uesugi M: Polyproline-rod approach to isolating protein targets of bioactive small molecules: isolation of a new target of indomethacin. J Am Chem Soc. 2007 Jan 31;129(4):873-80. Pubmed

7. Putative G-protein coupled receptor 44

Pharmacological action: unknown
Actions: other/unknown

Orphan receptor

Organism class: human
UniProt ID: Q9Y5Y4 Link_out
Gene: GPR44 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Hata AN, Lybrand TP, Breyer RM: Identification of determinants of ligand binding affinity and selectivity in the prostaglandin D2 receptor CRTH2. J Biol Chem. 2005 Sep 16;280(37):32442-51. Epub 2005 Jul 19. Pubmed
  2. Hata AN, Lybrand TP, Marnett LJ, Breyer RM: Structural determinants of arylacetic acid nonsteroidal anti-inflammatory drugs necessary for binding and activation of the prostaglandin D2 receptor CRTH2. Mol Pharmacol. 2005 Mar;67(3):640-7. Epub 2004 Nov 24. Pubmed
  3. Mathiesen JM, Ulven T, Martini L, Gerlach LO, Heinemann A, Kostenis E: Identification of indole derivatives exclusively interfering with a G protein-independent signaling pathway of the prostaglandin D2 receptor CRTH2. Mol Pharmacol. 2005 Aug;68(2):393-402. Epub 2005 May 3. Pubmed
Enzymes

1. Cytochrome P450 2C19

Actions: substrate, inhibitor

Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine

UniProt ID: P33261 Link_out
Gene: CYP2C19 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed

2. Cytochrome P450 2C9

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S- warfarin, diclofenac, phenytoin, tolbutamide and losartan

UniProt ID: P11712 Link_out
Gene: CYP2C9
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed

3. Liver carboxylesterase 1

Actions: substrate

Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs. Hydrolyzes aromatic and aliphatic esters, but has no catalytic activity toward amides or a fatty acyl CoA ester

UniProt ID: P23141 Link_out
Gene: CES1
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. 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. Mano Y, Usui T, Kamimura H: Contribution of UDP-glucuronosyltransferases 1A9 and 2B7 to the glucuronidation of indomethacin in the human liver. Eur J Clin Pharmacol. 2007 Mar;63(3):289-96. Epub 2007 Jan 24. Pubmed

5. UDP-glucuronosyltransferase 1-1

Actions: substrate, inhibitor

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. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  2. Mano Y, Usui T, Kamimura H: In vitro inhibitory effects of non-steroidal antiinflammatory drugs on UDP-glucuronosyltransferase 1A1-catalysed estradiol 3beta-glucuronidation in human liver microsomes. Biopharm Drug Dispos. 2005 Jan;26(1):35-9. Pubmed

6. UDP-glucuronosyltransferase 2B7

Actions: substrate, inhibitor

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. Mano Y, Usui T, Kamimura H: Contribution of UDP-glucuronosyltransferases 1A9 and 2B7 to the glucuronidation of indomethacin in the human liver. Eur J Clin Pharmacol. 2007 Mar;63(3):289-96. Epub 2007 Jan 24. Pubmed
  2. Mano Y, Usui T, Kamimura H: Inhibitory potential of nonsteroidal anti-inflammatory drugs on UDP-glucuronosyltransferase 2B7 in human liver microsomes. Eur J Clin Pharmacol. 2007 Feb;63(2):211-6. Epub 2007 Jan 3. Pubmed
Transporters

1. Canalicular multispecific organic anion transporter 2

Actions: inhibitor

May act as an inducible transporter in the biliary and intestinal excretion of organic anions

UniProt ID: O15438 Link_out
Gene: ABCC3 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Zelcer N, Saeki T, Reid G, Beijnen JH, Borst P: Characterization of drug transport by the human multidrug resistance protein 3 (ABCC3). J Biol Chem. 2001 Dec 7;276(49):46400-7. Pubmed
  2. Gedeon C, Behravan J, Koren G, Piquette-Miller M: Transport of glyburide by placental ABC transporters: implications in fetal drug exposure. Placenta. 2006 Nov-Dec;27(11-12):1096-102. Epub 2006 Feb 3. Pubmed

2. Multidrug resistance-associated protein 4

Actions: inhibitor

May be an organic anion pump relevant to cellular detoxification

UniProt ID: O15439 Link_out
Gene: ABCC4 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Reid G, Wielinga P, Zelcer N, van der Heijden I, Kuil A, de Haas M, Wijnholds J, Borst P: The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs. Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9244-9. Epub 2003 Jun 30. Pubmed
  2. Bai J, Lai L, Yeo HC, Goh BC, Tan TM: Multidrug resistance protein 4 (MRP4/ABCC4) mediates efflux of bimane-glutathione. Int J Biochem Cell Biol. 2004 Feb;36(2):247-57. Pubmed
  3. Ose A, Ito M, Kusuhara H, Yamatsugu K, Kanai M, Shibasaki M, Hosokawa M, Schuetz JD, Sugiyama Y: Limited brain distribution of [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxyl ate phosphate (Ro 64-0802), a pharmacologically active form of oseltamivir, by active efflux across the blood-brain barrier mediated by organic anion transporter 3 (Oat3/Slc22a8) and multidrug resistance-associated protein 4 (Mrp4/Abcc4). Drug Metab Dispos. 2009 Feb;37(2):315-21. Epub 2008 Nov 24. Pubmed

3. Multidrug resistance-associated protein 6

Actions: inhibitor

May participate directly in the active transport of drugs into subcellular organelles or influence drug distribution indirectly. Transports glutathione conjugates as leukotriene-c4 (LTC4) and N-ethylmaleimide S-glutathione (NEM-GS)

UniProt ID: O95255 Link_out
Gene: ABCC6 Link_out
Protein Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Ilias A, Urban Z, Seidl TL, Le Saux O, Sinko E, Boyd CD, Sarkadi B, Varadi A: Loss of ATP-dependent transport activity in pseudoxanthoma elasticum-associated mutants of human ABCC6 (MRP6). J Biol Chem. 2002 May 10;277(19):16860-7. Epub 2002 Mar 5. Pubmed

4. Multidrug resistance protein 1

Actions: substrate, inhibitor

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Wang EJ, Casciano CN, Clement RP, Johnson WW: Active transport of fluorescent P-glycoprotein substrates: evaluation as markers and interaction with inhibitors. Biochem Biophys Res Commun. 2001 Nov 30;289(2):580-5. Pubmed
  2. Faassen F, Vogel G, Spanings H, Vromans H: Caco-2 permeability, P-glycoprotein transport ratios and brain penetration of heterocyclic drugs. Int J Pharm. 2003 Sep 16;263(1-2):113-22. Pubmed

5. Multidrug resistance-associated protein 1

Actions: inhibitor

May participate directly in the active transport of drugs into subcellular organelles or influence drug distribution indirectly. Confers resistance to anticancer drugs. Transports LTC4. May protect milk against xenobiotics

UniProt ID: P33527 Link_out
Gene: ABCC1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Evers R, de Haas M, Sparidans R, Beijnen J, Wielinga PR, Lankelma J, Borst P: Vinblastine and sulfinpyrazone export by the multidrug resistance protein MRP2 is associated with glutathione export. Br J Cancer. 2000 Aug;83(3):375-83. Pubmed
  2. Hong J, Lambert JD, Lee SH, Sinko PJ, Yang CS: Involvement of multidrug resistance-associated proteins in regulating cellular levels of (-)-epigallocatechin-3-gallate and its methyl metabolites. Biochem Biophys Res Commun. 2003 Oct 10;310(1):222-7. Pubmed
  3. Ilias A, Urban Z, Seidl TL, Le Saux O, Sinko E, Boyd CD, Sarkadi B, Varadi A: Loss of ATP-dependent transport activity in pseudoxanthoma elasticum-associated mutants of human ABCC6 (MRP6). J Biol Chem. 2002 May 10;277(19):16860-7. Epub 2002 Mar 5. Pubmed
  4. Reid G, Wielinga P, Zelcer N, van der Heijden I, Kuil A, de Haas M, Wijnholds J, Borst P: The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs. Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9244-9. Epub 2003 Jun 30. Pubmed
  5. Gedeon C, Behravan J, Koren G, Piquette-Miller M: Transport of glyburide by placental ABC transporters: implications in fetal drug exposure. Placenta. 2006 Nov-Dec;27(11-12):1096-102. Epub 2006 Feb 3. Pubmed

6. Solute carrier organic anion transporter family member 1A2

Actions: substrate, inhibitor

Mediates the Na(+)-independent transport of organic anions such as sulfobromophthalein (BSP) and conjugated (taurocholate) and unconjugated (cholate) bile acids (By similarity)

UniProt ID: P46721 Link_out
Gene: SLCO1A2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Shitara Y, Sugiyama D, Kusuhara H, Kato Y, Abe T, Meier PJ, Itoh T, Sugiyama Y: Comparative inhibitory effects of different compounds on rat oatpl (slc21a1)- and Oatp2 (Slc21a5)-mediated transport. Pharm Res. 2002 Feb;19(2):147-53. Pubmed
  2. Kouzuki H, Suzuki H, Sugiyama Y: Pharmacokinetic study of the hepatobiliary transport of indomethacin. Pharm Res. 2000 Apr;17(4):432-8. Pubmed

7. Solute carrier family 22 member 6

Actions: inhibitor
UniProt ID: Q4U2R8 Link_out
Gene: hROAT1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Mulato AS, Ho ES, Cihlar T: Nonsteroidal anti-inflammatory drugs efficiently reduce the transport and cytotoxicity of adefovir mediated by the human renal organic anion transporter 1. J Pharmacol Exp Ther. 2000 Oct;295(1):10-5. Pubmed
  2. Jung KY, Takeda M, Kim DK, Tojo A, Narikawa S, Yoo BS, Hosoyamada M, Cha SH, Sekine T, Endou H: Characterization of ochratoxin A transport by human organic anion transporters. Life Sci. 2001 Sep 21;69(18):2123-35. Pubmed
  3. Takeda M, Khamdang S, Narikawa S, Kimura H, Hosoyamada M, Cha SH, Sekine T, Endou H: Characterization of methotrexate transport and its drug interactions with human organic anion transporters. J Pharmacol Exp Ther. 2002 Aug;302(2):666-71. Pubmed
  4. Hosoyamada M, Sekine T, Kanai Y, Endou H: Molecular cloning and functional expression of a multispecific organic anion transporter from human kidney. Am J Physiol. 1999 Jan;276(1 Pt 2):F122-8. Pubmed
  5. Lu R, Chan BS, Schuster VL: Cloning of the human kidney PAH transporter: narrow substrate specificity and regulation by protein kinase C. Am J Physiol. 1999 Feb;276(2 Pt 2):F295-303. Pubmed
  6. Sandhu P, Lee W, Xu X, Leake BF, Yamazaki M, Stone JA, Lin JH, Pearson PG, Kim RB: Hepatic uptake of the novel antifungal agent caspofungin. Drug Metab Dispos. 2005 May;33(5):676-82. Epub 2005 Feb 16. Pubmed
  7. Kuze K, Graves P, Leahy A, Wilson P, Stuhlmann H, You G: Heterologous expression and functional characterization of a mouse renal organic anion transporter in mammalian cells. J Biol Chem. 1999 Jan 15;274(3):1519-24. Pubmed
  8. Uwai Y, Saito H, Inui K: Interaction between methotrexate and nonsteroidal anti-inflammatory drugs in organic anion transporter. Eur J Pharmacol. 2000 Dec 1;409(1):31-6. Pubmed
  9. Apiwattanakul N, Sekine T, Chairoungdua A, Kanai Y, Nakajima N, Sophasan S, Endou H: Transport properties of nonsteroidal anti-inflammatory drugs by organic anion transporter 1 expressed in Xenopus laevis oocytes. Mol Pharmacol. 1999 May;55(5):847-54. Pubmed

8. Solute carrier family 22 member 8

Actions: inhibitor

Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenadine. Transports benzylpenicillin (PCG), estrone- 3-sulfate (E1S), cimetidine (CMD), 2,4-dichloro-phenoxyacetate (2,4-D), p-amino-hippurate (PAH), acyclovir (ACV) and ochratoxin (OTA)

UniProt ID: Q8TCC7 Link_out
Gene: SLC22A8 Link_out
Protein Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Cha SH, Sekine T, Fukushima JI, Kanai Y, Kobayashi Y, Goya T, Endou H: Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney. Mol Pharmacol. 2001 May;59(5):1277-86. Pubmed
  2. Jung KY, Takeda M, Kim DK, Tojo A, Narikawa S, Yoo BS, Hosoyamada M, Cha SH, Sekine T, Endou H: Characterization of ochratoxin A transport by human organic anion transporters. Life Sci. 2001 Sep 21;69(18):2123-35. Pubmed
  3. Takeda M, Khamdang S, Narikawa S, Kimura H, Hosoyamada M, Cha SH, Sekine T, Endou H: Characterization of methotrexate transport and its drug interactions with human organic anion transporters. J Pharmacol Exp Ther. 2002 Aug;302(2):666-71. Pubmed
  4. Ohtsuki S, Kikkawa T, Mori S, Hori S, Takanaga H, Otagiri M, Terasaki T: Mouse reduced in osteosclerosis transporter functions as an organic anion transporter 3 and is localized at abluminal membrane of blood-brain barrier. J Pharmacol Exp Ther. 2004 Jun;309(3):1273-81. Epub 2004 Feb 4. Pubmed
  5. Mori S, Takanaga H, Ohtsuki S, Deguchi T, Kang YS, Hosoya K, Terasaki T: Rat organic anion transporter 3 (rOAT3) is responsible for brain-to-blood efflux of homovanillic acid at the abluminal membrane of brain capillary endothelial cells. J Cereb Blood Flow Metab. 2003 Apr;23(4):432-40. Pubmed
  6. Kusuhara H, Sekine T, Utsunomiya-Tate N, Tsuda M, Kojima R, Cha SH, Sugiyama Y, Kanai Y, Endou H: Molecular cloning and characterization of a new multispecific organic anion transporter from rat brain. J Biol Chem. 1999 May 7;274(19):13675-80. Pubmed

9. Canalicular multispecific organic anion transporter 1

Actions: substrate, inhibitor

Mediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter

UniProt ID: Q92887 Link_out
Gene: ABCC2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Gedeon C, Behravan J, Koren G, Piquette-Miller M: Transport of glyburide by placental ABC transporters: implications in fetal drug exposure. Placenta. 2006 Nov-Dec;27(11-12):1096-102. Epub 2006 Feb 3. Pubmed
  2. Dahan A, Amidon GL: Small intestinal efflux mediated by MRP2 and BCRP shifts sulfasalazine intestinal permeability from high to low, enabling its colonic targeting. Am J Physiol Gastrointest Liver Physiol. 2009 Aug;297(2):G371-7. Epub 2009 Jun 18. Pubmed
  3. Dahan A, Sabit H, Amidon GL: The H2 receptor antagonist nizatidine is a P-glycoprotein substrate: characterization of its intestinal epithelial cell efflux transport. AAPS J. 2009 Jun;11(2):205-13. Epub 2009 Mar 25. Pubmed
  4. Kouzuki H, Suzuki H, Sugiyama Y: Pharmacokinetic study of the hepatobiliary transport of indomethacin. Pharm Res. 2000 Apr;17(4):432-8. Pubmed

10. ATP-binding cassette transporter sub-family C member 11

Actions: inhibitor

Participates in physiological processes involving bile acids, conjugated steroids and cyclic nucleotides. Enhances the cellular extrusion of cAMP and cGMP. Stimulates the ATP-dependent uptake of a range of physiological and synthetic lipophilic anions, including the glutathione S-conjugates leukotriene C4 and dinitrophenyl S-glutathione, steroid sulfates such as dehydroepiandrosterone 3-sulfate (DHEAS) and estrone 3-sulfate, glucuronides such as estradiol 17-beta-D-glucuronide (E(2)17betaG), the monoanionic bile acids glycocholate and taurocholate, and methotrexate. Probably functions to secrete earwax

UniProt ID: Q96J66 Link_out
Gene: ABCC11 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chen ZS, Guo Y, Belinsky MG, Kotova E, Kruh GD: Transport of bile acids, sulfated steroids, estradiol 17-beta-D-glucuronide, and leukotriene C4 by human multidrug resistance protein 8 (ABCC11). Mol Pharmacol. 2005 Feb;67(2):545-57. Epub 2004 Nov 10. Pubmed

11. Solute carrier family 22 member 11

Actions: inhibitor

Mediates saturable uptake of estrone sulfate, dehydroepiandrosterone sulfate and related compounds

UniProt ID: Q9NSA0 Link_out
Gene: SLC22A11 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Babu E, Takeda M, Narikawa S, Kobayashi Y, Enomoto A, Tojo A, Cha SH, Sekine T, Sakthisekaran D, Endou H: Role of human organic anion transporter 4 in the transport of ochratoxin A. Biochim Biophys Acta. 2002 Jun 12;1590(1-3):64-75. Pubmed
  2. Takeda M, Khamdang S, Narikawa S, Kimura H, Hosoyamada M, Cha SH, Sekine T, Endou H: Characterization of methotrexate transport and its drug interactions with human organic anion transporters. J Pharmacol Exp Ther. 2002 Aug;302(2):666-71. Pubmed
  3. Cha SH, Sekine T, Kusuhara H, Yu E, Kim JY, Kim DK, Sugiyama Y, Kanai Y, Endou H: Molecular cloning and characterization of multispecific organic anion transporter 4 expressed in the placenta. J Biol Chem. 2000 Feb 11;275(6):4507-12. Pubmed

12. Sodium/bile acid cotransporter

Actions: substrate

The hepatic sodium/bile acid uptake system exhibits broad substrate specificity and transports various non-bile acid organic compounds as well. It is strictly dependent on the extracellular presence of sodium

UniProt ID: Q14973 Link_out
Gene: SLC10A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Kouzuki H, Suzuki H, Sugiyama Y: Pharmacokinetic study of the hepatobiliary transport of indomethacin. Pharm Res. 2000 Apr;17(4):432-8. Pubmed

13. Solute carrier family 22 member 7

Actions: substrate

Mediates sodium-independent multispecific organic anion transport. Transport of prostaglandin E2, prostaglandin F2, tetracycline, bumetanide, estrone sulfate, glutarate, dehydroepiandrosterone sulfate, allopurinol, 5-fluorouracil, paclitaxel, L-ascorbic acid, salicylate, ethotrexate, and alpha- ketoglutarate

UniProt ID: Q9Y694 Link_out
Gene: SLC22A7 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Morita N, Kusuhara H, Sekine T, Endou H, Sugiyama Y: Functional characterization of rat organic anion transporter 2 in LLC-PK1 cells. J Pharmacol Exp Ther. 2001 Sep;298(3):1179-84. Pubmed
Carriers

1. Serum albumin

Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood

UniProt ID: P02768 Link_out
Gene: ALB Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Bertucci C, Wainer IW: Improved chromatographic performance of a modified human albumin based stationary phase. Chirality. 1997;9(4):335-40. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on July 27, 2011 18:07

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.