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Identification
NameIndomethacin
Accession NumberDB00328  (APRD00109)
TypeSmall Molecule
GroupsApproved, Investigational
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
Synonyms
SynonymLanguageCode
{1-[(4-chlorophenyl)carbonyl]-5-methoxy-2-methyl-1H-indol-3-yl}acetic acidNot AvailableNot Available
1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acidNot AvailableNot Available
AconipNot AvailableNot Available
IndocinNot AvailableNot Available
IndometacinNot AvailableNot Available
IndometacinaNot AvailableNot Available
IndometacineNot AvailableNot Available
IndometacinumNot AvailableNot Available
IndomethacinNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
ArthrexinAlphapharm
ElmetacinSankyo
IndaflexAndromaco
IndocidLundbeck
IndocinLundbeck
Indolar SRSandoz
IndomedGreater Pharma
IndoxenQuality Pharmaceutical
MetindolGlaxoSmithKline
MikametanMikasa Seiyaku
Nu-IndoNu-Pharm
ReumacideVitória
TivorbexNot Available
Brand mixturesNot Available
Categories
CAS number53-86-1
WeightAverage: 357.788
Monoisotopic: 357.076785712
Chemical FormulaC19H16ClNO4
InChI KeyCGIGDMFJXJATDK-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)
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
Mass Specshow(7.7 KB)
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassIndoles and Derivatives
SubclassBenzoylindoles
Direct parentBenzoylindoles
Alternative parentsIndole-3-acetic Acid Derivatives; Indolecarboxylic Acids and Derivatives; Benzamides; Indoles; Benzoyl Derivatives; Anisoles; Alkyl Aryl Ethers; Chlorobenzenes; N-substituted Pyrroles; Aryl Chlorides; Carboxylic Acids; Enolates; Polyamines; Carboxylic Acid Amides; Organochlorides
Substituentsindole-3-acetic acid derivative; indolecarboxylic acid derivative; indolyl carboxylic acid derivative; benzamide; indole; benzoyl; anisole; phenol ether; alkyl aryl ether; chlorobenzene; aryl chloride; aryl halide; n-substituted pyrrole; substituted pyrrole; benzene; pyrrole; carboxamide group; polyamine; carboxylic acid; carboxylic acid derivative; ether; enolate; amine; organochloride; organohalogen; organonitrogen compound
Classification descriptionThis compound belongs to the benzoylindoles. These are organic compounds containing an indole attached to a benzoyl moeity through the acyl group.
Pharmacology
IndicationFor 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.
PharmacodynamicsIndomethacin, 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 actionIndomethacin 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.
AbsorptionBioavailability is approximately 100% following oral administration and 80–90% following rectal administration.
Volume of distributionNot Available
Protein binding97%
Metabolism

Hepatic.

SubstrateEnzymesProduct
Indomethacin
O-DesmethylindomethacinDetails
Indomethacin
Indomethacin acyl glucuronideDetails
Indomethacin
N-Deschlorobenzoyl indomethacinDetails
N-Deschlorobenzoyl indomethacin
Not Available
O-Desmethyl-N-deschlorobenzoyl indomethacinDetails
Route of eliminationIndomethacin is eliminated via renal excretion, metabolism, and biliary excretion.
Half life4.5 hours
ClearanceNot Available
ToxicityThe 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
PathwayCategorySMPDB ID
Indomethacin Action PathwayDrug actionSMP00104
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9509
Blood Brain Barrier + 0.9381
Caco-2 permeable + 0.5857
P-glycoprotein substrate Non-substrate 0.636
P-glycoprotein inhibitor I Non-inhibitor 0.9313
P-glycoprotein inhibitor II Non-inhibitor 0.834
Renal organic cation transporter Non-inhibitor 0.8334
CYP450 2C9 substrate Non-substrate 0.712
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Substrate 0.6436
CYP450 1A2 substrate Inhibitor 0.9107
CYP450 2C9 substrate Non-inhibitor 0.9071
CYP450 2D6 substrate Non-inhibitor 0.9302
CYP450 2C19 substrate Non-inhibitor 0.9025
CYP450 3A4 substrate Non-inhibitor 0.8309
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.6978
Ames test Non AMES toxic 0.9133
Carcinogenicity Non-carcinogens 0.8728
Biodegradation Not ready biodegradable 0.9743
Rat acute toxicity 4.0722 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9818
hERG inhibition (predictor II) Non-inhibitor 0.8306
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
FormRouteStrength
CapsuleOral25 mg
CapsuleOral50 mg
Capsule, extended releaseOral75 mg
InjectionIntravenous1 mg
SuppositoryRectal100 mg
SuppositoryRectal50 mg
SuspensionOral25 mg/5 ml
Prices
Unit descriptionCostUnit
Indocin i.v. 1 mg vial642.6USDvial
Indomethacin 1 mg vial600.0USDvial
Indocin 50 mg suppository9.56USDsuppository
Indomethacin CR 75 mg capsule3.12USDcapsule
Indocin sr 75 mg capsule2.92USDcapsule
Indomethacin powder2.57USDg
Ratio-Indomethacin 100 mg Suppository0.93USDsuppository
Sandoz Indomethacin 100 mg Suppository0.93USDsuppository
Sandoz Indomethacin 50 mg Suppository0.93USDsuppository
Indomethacin 50 mg capsule0.65USDcapsule
Indomethacin 25 mg capsule0.44USDcapsule
Apo-Indomethacin 50 mg Capsule0.16USDcapsule
Novo-Methacin 50 mg Capsule0.16USDcapsule
Nu-Indo 50 mg Capsule0.16USDcapsule
Apo-Indomethacin 25 mg Capsule0.09USDcapsule
Novo-Methacin 25 mg Capsule0.09USDcapsule
Nu-Indo 25 mg Capsule0.09USDcapsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point151U.S. Patent 3,161,654.
water solubility0.937 mg/L (at 25 °C)YALKOWSKY,SH & DANNENFELSER,RM (1992)
logP4.27HANSCH,C ET AL. (1995)
logS-4.62ADME Research, USCD
Caco2 permeability-4.69ADME Research, USCD
pKa4.5BUDAVARI,S ET AL. (1989)
Predicted Properties
PropertyValueSource
Water Solubility0.0024ALOGPS
logP4.25ALOGPS
logP3.53ChemAxon
logS-5.2ALOGPS
pKa (Strongest Acidic)3.8ChemAxon
pKa (Strongest Basic)-2.3ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area68.53 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity94.81 m3·mol-1ChemAxon
Polarizability36.64 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Spectra
Spectra1D NMR
References
Synthesis Reference

Hubertus L. Regtop, John R. Biffin, “Preparation of divalent metal salts of indomethacin.” U.S. Patent US5310936, issued November, 1917.

US5310936
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
ResourceLink
KEGG DrugD00141
KEGG CompoundC01926
PubChem Compound3715
PubChem Substance46508291
ChemSpider3584
BindingDB17638
ChEBI5918
ChEMBLCHEMBL6
Therapeutic Targets DatabaseDAP000617
PharmGKBPA449982
IUPHAR1909
Guide to Pharmacology1909
Drug Product Database2143372
RxListhttp://www.rxlist.com/cgi/generic/indometh.htm
Drugs.comhttp://www.drugs.com/cdi/indomethacin.html
WikipediaIndomethacin
ATC CodesM01AB01C01EB03
AHFS Codes
  • 28:08.04.92
PDB EntriesNot Available
FDA labelshow(56.2 KB)
MSDSshow(73.2 KB)
Interactions
Drug Interactions
Drug
AcebutololRisk of inhibition of renal prostaglandins
AcenocoumarolThe NSAID, indomethacin, may increase the anticoagulant effect of acenocoumarol.
AlendronateIncreased risk of gastric toxicity
AnisindioneThe NSAID, indomethacin, may increase the anticoagulant effect of anisindione.
AtenololRisk of inhibition of renal prostaglandins
Azilsartan medoxomilIncreases toxicity of each. May deteriorate renal function, particularly in volume depleted or elderly patients. Decreases effects of azilsartan by antagonism.
BetaxololNonsteroidal Anti-Inflammatory Agents such as indomethacin may diminish the antihypertensive effect of Beta-Blockers such as betaxolol. Monitor for increases in blood pressure if a nonsteroidal anti-inflammatory agent (NSAID) is initiated/dose increased, or decreases in blood pressure if a NSAID is discontinued/dose decreased; this is particularly important if NSAID treatment is for extended periods of time. Ophthalmic beta-blockers are likely of little concern.
BevantololRisk of inhibition of renal prostaglandins
BisoprololRisk of inhibition of renal prostaglandins
BumetanideThe NSAID, indomethacin, may decrease the diuretic and antihypertensive effects of the loop diuretic, bumetanide.
CarteololRisk of inhibition of renal prostaglandins
CarvedilolRisk of inhibition of renal prostaglandins
ColesevelamBile acid sequestrants may decrease the absorption of Nonsteroidal Anti-Inflammatory Agents. Monitor for decreased serum concentrations/therapeutic effects of nonsteroidal anti-inflammatory agents (NSAID) if coadministered with bile acid sequestrants. Separating the administration of doses by 2 or more hours may reduce (but not eliminate) the risk of interaction. The manufacturer of colesevelam recommends that drugs should be administered at least 1 hour before or 4 hours after colesevelam.
CyclosporineMonitor for nephrotoxicity
DicoumarolThe NSAID, indomethacin, may increase the anticoagulant effect of dicumarol.
DiflunisalConcomitant therapy with the two NSAIDs, indomethacin and diflunisal, increases the risk of NSAID-related adverse effects (e.g. GI ulcers, bleeds, increased blood pressure).
EltrombopagIncreases levels of Indomethacin via metabolism decrease. UDP-glucuronosyltransferase inhibition with unclear significance.
EsmololRisk of inhibition of renal prostaglandins
Ethacrynic acidThe NSAID, indomethacin, may decrease the diuretic and antihypertensive effects of the loop diuretic, ethacrynic acid.
FurosemideThe NSAID, indomethacin, may decrease the diuretic and antihypertensive effects of the loop diuretic, furosemide.
Ginkgo bilobaAdditive anticoagulant/antiplatelet effects may increase bleed risk. Concomitant therapy should be avoided.
Glucagon recombinantMonitor therapy due to diminished therapeutic effect of glucagon.
LabetalolRisk of inhibition of renal prostaglandins
LithiumThe NSAID, indomethacin, may decrease the renal excretion of lithium. Increased risk of lithium toxicity.
LosartanIndomethacin decreases the effect of losartan
MethotrexateThe NSAID, indomethacin, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.
MetoprololRisk of inhibition of renal prostaglandins
NadololRisk of inhibition of renal prostaglandins
OxprenololRisk of inhibition of renal prostaglandins
PenbutololRisk of inhibition of renal prostaglandins
PindololRisk of inhibition of renal prostaglandins
PractololRisk of inhibition of renal prostaglandins
PralatrexateNSAIDs increase the risk of toxicity due to impairment of renal clearance of pralatrexate thus increasing exposure. Monitor for adverse effects or adjust dose of pralatrexate.
ProbenecidProbenecid increases the effect/toxicity of indomethacin
PropranololRisk of inhibition of renal prostaglandins
SotalolRisk of inhibition of renal prostaglandins
TamoxifenIndomethacin may reduce clearance rate of Tamoxifen. Monitor for changes in therapeutic/adverse effects of Tamoxifen if Indomethacin is initiated, discontinued or dose changed.
TelmisartanConcomitant use of Telmisartan and Indomethacin may increase the risk of acute renal failure and hyperkalemia. Monitor renal function at the beginning and during treatment.
TimololRisk of inhibition of renal prostaglandins
TolbutamideIndomethacin, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Tolbutamide, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in Tolbutamide therapeutic and adverse effects if Indomethacin is initiated, discontinued or dose changed.
TorasemideThe NSAID, indomethacin, may decrease the diuretic and antihypertensive effects of the loop diuretic, torasemide.
TrandolaprilThe NSAID, Indomethacin, may reduce the antihypertensive effect of Trandolapril. Consider alternate therapy or monitor for changes in Trandolapril efficacy if Indomethacin is initiated, discontinued or dose changed.
TreprostinilThe prostacyclin analogue, Treprostinil, may increase the risk of bleeding when combined with the NSAID, Indomethacin. Monitor for increased bleeding during concomitant thearpy.
TriamtereneRisk of acute renal impairment with this combination
TrimethoprimThe strong CYP2C9 inhibitor, Indomethacine, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Indomethacine is initiated, discontinued or dose changed.
VoriconazoleIndomethacin, a strong CYP2C9 inhibitor, may increase the serum concentration of voriconazole by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of voriconazole if indomethacin is initiated, discontinued or dose changed.
WarfarinIndomethacin, a strong CYP2C9 inhibitor, may decrease the metabolism of warfarin. The antiplatelet effect of indomethacin may also increase the bleed risk associated with warfarin. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of warfarin if indomethacin is initiated, discontinued or dose changed.
Food Interactions
  • Avoid alcohol.
  • Take with food or antacids to reduce irritation.

Targets

1. Prostaglandin G/H synthase 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Prostaglandin G/H synthase 1 P23219 Details

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

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Prostaglandin G/H synthase 2 P35354 Details

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

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Phospholipase A2, membrane associated P14555 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Prostaglandin reductase 2 Q8N8N7 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: activator

Components

Name UniProt ID Details
Peroxisome proliferator-activated receptor gamma P37231 Details

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
  2. Lehmann JM, Lenhard JM, Oliver BB, Ringold GM, Kliewer SA: Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J Biol Chem. 1997 Feb 7;272(6):3406-10. Pubmed

6. Lactoylglutathione lyase

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Lactoylglutathione lyase Q04760 Details

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. Prostaglandin D2 receptor 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: other/unknown

Components

Name UniProt ID Details
Prostaglandin D2 receptor 2 Q9Y5Y4 Details

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

8. Peroxisome proliferator-activated receptor alpha

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: agonist

Components

Name UniProt ID Details
Peroxisome proliferator-activated receptor alpha Q07869 Details

References:

  1. Lehmann JM, Lenhard JM, Oliver BB, Ringold GM, Kliewer SA: Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J Biol Chem. 1997 Feb 7;272(6):3406-10. Pubmed

Enzymes

1. Cytochrome P450 2C19

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C19 P33261 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Liver carboxylesterase 1 P23141 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

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

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

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

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 2B7 P16662 Details

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

Carriers

1. Serum albumin

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Serum albumin P02768 Details

References:

  1. Bertucci C, Wainer IW: Improved chromatographic performance of a modified human albumin based stationary phase. Chirality. 1997;9(4):335-40. Pubmed

Transporters

1. Canalicular multispecific organic anion transporter 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Canalicular multispecific organic anion transporter 2 O15438 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Multidrug resistance-associated protein 4 O15439 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Multidrug resistance-associated protein 6 O95255 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Multidrug resistance-associated protein 1 P33527 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Solute carrier organic anion transporter family member 1A2 P46721 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Solute carrier family 22 member 6 Q4U2R8 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Solute carrier family 22 member 8 Q8TCC7 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Canalicular multispecific organic anion transporter 1 Q92887 Details

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 sub-family C member 11

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
ATP-binding cassette sub-family C member 11 Q96J66 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Solute carrier family 22 member 11 Q9NSA0 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Sodium/bile acid cotransporter Q14973 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Solute carrier family 22 member 7 Q9Y694 Details

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

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:09