Banner
Identification
Name Etodolac
Accession Number DB00749 (APRD00067)
Type small molecule
Groups approved
Description

Etodolac is a non-steroidal anti-inflammatory drug (NSAID) with anti-inflammatory, analgesic and antipyretic properties. Its therapeutic effects are due to its ability to inhibit prostaglandin synthesis. It is indicated for relief of signs and symptoms of rheumatoid arthritis and osteoarthritis.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • etodolac
Brand names
  • Etodolac [Usan:Ban:Inn]
  • Etodolacetodolic acid
  • Etodolaco [INN-Spanish]
  • Etodolacum [INN-Latin]
  • Etodolic Acid
  • Lodine
  • Lodine XL
  • Ultradol
Brand name mixtures Not Available
Categories
  • Anti-inflammatory Agents
  • Cyclooxygenase Inhibitors
  • Analgesics
  • Analgesics, Non-Narcotic
  • Antipyretics
  • Nonsteroidal Anti-inflammatory Agents (NSAIAs)
CAS number 41340-25-4
Weight Average: 287.3535
Monoisotopic: 287.152143543
Chemical Formula C17H21NO3
InChI Key InChIKey=NNYBQONXHNTVIJ-UHFFFAOYSA-N
InChI
InChI=1S/C17H21NO3/c1-3-11-6-5-7-12-13-8-9-21-17(4-2,10-14(19)20)16(13)18-15(11)12/h5-7,18H,3-4,8-10H2,1-2H3,(H,19,20)
Plain Text
IUPAC Name
2-{1,8-diethyl-1H,3H,4H,9H-pyrano[3,4-b]indol-1-yl}acetic acid
SMILES
CCC1=CC=CC2=C1NC1=C2CCOC1(CC)CC(O)=O
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Indoles and Indole Derivatives
Substructures
  • Hydroxy Compounds
  • Pyrans
  • Acetates
  • Indoles and Indole Derivatives
  • Pyrroles
  • Ethers
  • Benzene and Derivatives
  • Carboxylic Acids and Derivatives
  • Heterocyclic compounds
  • Aromatic compounds
  • Imines
Pharmacology
Indication For acute and long-term management of signs and symptoms of osteoarthritis and rheumatoid arthritis, as well as for the management of pain.
Pharmacodynamics Etodolac is an anti-inflammatory agent with analgesic and antipyretic properties. It is used to treat osteoarthritis, rheumatoid arthritis and control acute pain. The therapeutic effects of etodolac are achieved via inhibition of the synthesis of prostaglandins involved in fever, pain, swelling and inflammation. Etodolac is administered as a racemate. As with other NSAIDs, the S-form has been shown to be active while the R-form is inactive. Both enantiomers are stable and there is no evidence of R- to S- conversion in vivo.
Mechanism of action Similar to other NSAIDs, the anti-inflammatory effects of etodolac result from inhibition of the enzyme cycooxygenase (COX). This decreases the synthesis of peripheral prostaglandins involved in mediating inflammation. Etodolac binds to the upper portion of the COX enzyme active site and prevents its substrate, arachidonic acid, from entering the active site. Etodolac was previously thought to be a non-selective COX inhibitor, but it is now known to be 5 – 50 times more selective for COX-2 than COX-1. Antipyresis may occur by central action on the hypothalamus, resulting in peripheral dilation, increased cutaneous blood flow, and subsequent heat loss.
Absorption Based on mass balance studies, the systemic bioavailability of etodolac from either the tablet or capsule formulation is at least 80%.
Volume of distribution
  • 390 mL/kg
Protein binding > 99% bound, primarily to albumin
Metabolism

Etodolac is extensively metabolized in the liver. Renal elimination of etodolac and its metabolites is the primary route of excretion (72%). Metabolites found in urine (with percents of the administered dose) are: unchanged etodolac (1%), etodolac glucuronide (13%), hydroxylated metabolites (6-, 7-, and 8-OH; 5%), hydroxylated metabolite glucuronides (20%), and unidentified metabolites (33%). Fecal excretion accounts for 16% of its elimination.

Enzyme Metabolite Reaction Km Vmax
Cytochrome P450 2C9 6-Hydroxyetodolac 6-hydroxylation
Cytochrome P450 2C9 7-Hydroxyetodolac 7-hydroxylation
UDP-glucuronosyltransferase 1-9 Etodolac acyl glucuronide glucuronidation
UDP-glucuronosyltransferase 1-3 Etodolac acyl glucuronide glucuronidation
UDP-glucuronosyltransferase 1-10 Etodolac acyl glucuronide glucuronidation
UDP-glucuronosyltransferase 2B7 Etodolac acyl glucuronide glucuronidation
Route of elimination It is not known whether etodolac is excreted in human milk; however, based on its physical-chemical properties, excretion into breast milk is expected. Etodolac is extensively metabolized in the liver. The hydroxylated-etodolac metabolites undergo further glucuronidation followed by renal excretion and partial elimination in the feces (16% of dose). Approximately 1% of a etodolac dose is excreted unchanged in the urine with 72% of the dose excreted into urine as parent drug plus metabolite.
Half life Terminal t1/2, 7.3 ± 4.0 hours. Distribution t1/2, 0.71 ± 0.50 hours
Clearance
  • Oral cl=49.1 mL/h/kg [Normal healthy adults]
  • Oral cl=49.4 mL/h/kg [Healthy males (18-65 years)]
  • Oral cl=35.7 mL/h/kg [Healthy females (27-65 years)]
  • Oral cl=45.7 mL/h/kg [Eldery (>65 years)]
  • Oral cl=58.3 mL/h/kg [Renal impairement (46-73 years)]
  • Oral cl=42.0 mL/h/kg [Hepatic impairement (34-60 years)]
Toxicity Selective COX-2 inhibitors have been associated with increased risk of serious cardiovascular events (e.g. myocardial infarction, stroke) in some patients. Current data is insufficient to assess the cardiovascular risk of etodolac. Etodolac may increase blood pressure and/or cause fluid retention and edema. Risk of GI toxicity including bleeding, ulceration and perforation. Risk of direct renal injury, including renal papillary necrosis. Anaphylactoid and serious skin reactions (e.g. exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported. Common adverse events include abdominal pain, constipation, diarrhea, dyspepsia, flatulence, GI bleeding, GI perforation, nausea, peptic ulcer, vomiting, renal function abnormalities, anemia, dizziness, edema, liver function test abnormalities, headache, prolonged bleeding time, pruritus, rash, tinnitus. Symptoms of overdose include lethargy, drowsiness, nausea, vomiting, and epigastric pain.
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00084 Etodolac Pathway SMP00084
Pharmacoeconomics
Manufacturers
  • Aaipharma llc
  • Apotex inc
  • Endo pharmaceuticals inc
  • Genpharm inc
  • Ivax pharmaceuticals inc sub teva pharmaceuticals usa
  • Mylan pharmaceuticals inc
  • Sandoz inc
  • Taro pharmaceutical industries ltd
  • Teva pharmaceuticals usa inc
  • Watson laboratories inc
  • Wyeth pharmaceuticals inc
  • Point holdings inc
  • Watson laboratories inc florida
  • Actavis elizabeth llc
  • Apotex inc etobicoke site
  • Mylan laboratories inc
  • Ranbaxy laboratories ltd
Packagers
Dosage forms
Form Route Strength
Capsule Oral 200 mg
Capsule Oral 300 mg
Tablet Oral 400 mg
Tablet Oral 500 mg
Tablet, extended release Oral 400 mg
Tablet, extended release Oral 500 mg
Tablet, extended release Oral 600 mg
Prices
Unit description Cost Unit
Etodolac CR 600 mg 24 Hour tablet 2.76 USD tablet
Lodine 400 mg tablet 2.65 USD tablet
Lodine 500 mg tablet 1.8 USD tablet
Etodolac CR 500 mg 24 Hour tablet 1.6 USD tablet
Etodolac 500 mg tablet 1.52 USD tablet
Etodolac 400 mg tablet 1.5 USD tablet
Etodolac CR 400 mg 24 Hour tablet 1.46 USD tablet
Etodolac 300 mg capsule 1.31 USD capsule
Apo-Etodolac 200 mg Capsule 0.8 USD capsule
Apo-Etodolac 300 mg Capsule 0.8 USD capsule
Patents Not Available
Properties
State solid
Melting point 145-148 oC
Experimental Properties
Property Value Source
water solubility 16 mg/L PhysProp
logP 2.5 PhysProp
pKa 4.65 Various sources
Predicted Properties
Property Value Source
water solubility 3.92e-02 g/l ALOGPS
logP 3.39 ALOGPS
logP 3.44 ChemAxon Molconvert
logS -3.87 ALOGPS
pKa 16.18 ChemAxon Molconvert
hydrogen acceptor count 3 ChemAxon Molconvert
hydrogen donor count 2 ChemAxon Molconvert
polar surface area 62.32 ChemAxon Molconvert
rotatable bond count 4 ChemAxon Molconvert
refractivity 81.16 ChemAxon Molconvert
polarizability 31.94 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D00315 Link_out
PubChem Compound 3308 Link_out
PubChem Substance 46505184 Link_out
ChemSpider 3192 Link_out
BindingDB 50016799 Link_out
ChEBI 4909 Link_out
ChEMBL 4909 Link_out
Therapeutic Targets Database DAP000778 Link_out
Drug Product Database 2242915 Link_out
RxList http://www.rxlist.com/cgi/generic/etodolac.htm Link_out
Drugs.com http://www.drugs.com/etodolac.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Etodolac Link_out
ATC Codes
  • M01AB08
AHFS Codes
  • 28:08.04.92
PDB Entries Not Available
FDA label show (289.6 KB)
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions
  • Avoid alcohol.
  • Food increases the peak plasma concentration of extended-release tablets with no effect on extent of absorption.
  • Food increases the time to peak concentration of regular release oral formulations by 1.4 to 3.8 hours with no effect on extent of absorption.
  • Take with food to reduce gastric irritation.
Targets

1. 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. Chen WS, Liu JH, Wei SJ, Liu JM, Hong CY, Yang WK: Colon cancer cells with high invasive potential are susceptible to induction of apoptosis by a selective COX-2 inhibitor. Cancer Sci. 2003 Mar;94(3):253-8. Pubmed
  2. Chen WS, Wei SJ, Liu JM, Hsiao M, Kou-Lin J, Yang WK: Tumor invasiveness and liver metastasis of colon cancer cells correlated with cyclooxygenase-2 (COX-2) expression and inhibited by a COX-2-selective inhibitor, etodolac. Int J Cancer. 2001 Mar 15;91(6):894-9. Pubmed
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  4. Kusuhara H, Komatsu H, Sumichika H, Sugahara K: Reactive oxygen species are involved in the apoptosis induced by nonsteroidal anti-inflammatory drugs in cultured gastric cells. Eur J Pharmacol. 1999 Nov 3;383(3):331-7. Pubmed
  5. Svendsen KB, Bech JN, Sorensen TB, Pedersen EB: A comparison of the effects of etodolac and ibuprofen on renal haemodynamics, tubular function, renin, vasopressin and urinary excretion of albumin and alpha-glutathione-S-transferase in healthy subjects: a placebo-controlled cross-over study. Eur J Clin Pharmacol. 2000 Aug;56(5):383-8. Pubmed
  6. Wilson JE, Chandrasekharan NV, Westover KD, Eager KB, Simmons DL: Determination of expression of cyclooxygenase-1 and -2 isozymes in canine tissues and their differential sensitivity to nonsteroidal anti-inflammatory drugs. Am J Vet Res. 2004 Jun;65(6):810-8. Pubmed

2. 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. Campbell NB, Jones SL, Blikslager AT: The effects of cyclo-oxygenase inhibitors on bile-injured and normal equine colon. Equine Vet J. 2002 Jul;34(5):493-8. Pubmed
  2. Glaser K, Sung ML, O’Neill K, Belfast M, Hartman D, Carlson R, Kreft A, Kubrak D, Hsiao CL, Weichman B: Etodolac selectively inhibits human prostaglandin G/H synthase 2 (PGHS-2) versus human PGHS-1. Eur J Pharmacol. 1995 Jul 25;281(1):107-11. Pubmed
  3. Hirate K, Uchida A, Ogawa Y, Arai T, Yoda K: Zaltoprofen, a non-steroidal anti-inflammatory drug, inhibits bradykinin-induced pain responses without blocking bradykinin receptors. Neurosci Res. 2006 Apr;54(4):288-94. Epub 2006 Feb 13. Pubmed
  4. Riendeau D, Percival MD, Boyce S, Brideau C, Charleson S, Cromlish W, Ethier D, Evans J, Falgueyret JP, Ford-Hutchinson AW, Gordon R, Greig G, Gresser M, Guay J, Kargman S, Leger S, Mancini JA, O’Neill G, Ouellet M, Rodger IW, Therien M, Wang Z, Webb JK, Wong E, Chan CC, et al.: Biochemical and pharmacological profile of a tetrasubstituted furanone as a highly selective COX-2 inhibitor. Br J Pharmacol. 1997 May;121(1):105-17. Pubmed – APRIL 26, 2010
  5. Wilson JE, Chandrasekharan NV, Westover KD, Eager KB, Simmons DL: Determination of expression of cyclooxygenase-1 and -2 isozymes in canine tissues and their differential sensitivity to nonsteroidal anti-inflammatory drugs. Am J Vet Res. 2004 Jun;65(6):810-8. Pubmed

3. Retinoic acid receptor RXR-alpha

Pharmacological action: unknown
Actions: other

Nuclear hormone receptor. Involved in the retinoic acid response pathway. Binds 9-cis retinoic acid (9C-RA). ARF6 acts as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer

Organism class: human
UniProt ID: P19793 Link_out
Gene: RXRA Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Kolluri SK, Corr M, James SY, Bernasconi M, Lu D, Liu W, Cottam HB, Leoni LM, Carson DA, Zhang XK: The R-enantiomer of the nonsteroidal antiinflammatory drug etodolac binds retinoid X receptor and induces tumor-selective apoptosis. Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2525-30. Epub 2005 Feb 7. Pubmed
Enzymes

1. Cytochrome P450 2C9

Actions: substrate, inhibitor

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
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. 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. 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. UDP-glucuronosyltransferase 1-3

Actions: substrate

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

UniProt ID: P35503 Link_out
Gene: UGT1A3 Link_out
Protein 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 1-10

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. 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

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. 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
Transporters

1. 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
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. Mignot I, Presle N, Lapicque F, Monot C, Dropsy R, Netter P: Albumin binding sites for etodolac enantiomers. Chirality. 1996;8(3):271-80. Pubmed
  2. Muller N, Lapicque F, Monot C, Payan E, Dropsy R, Netter P: Stereoselective binding of etodolac to human serum albumin. Chirality. 1992;4(4):240-6. Pubmed
  3. Smith PC, Song WQ, Rodriguez RJ: Covalent binding of etodolac acyl glucuronide to albumin in vitro. Drug Metab Dispos. 1992 Nov-Dec;20(6):962-5. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on April 19, 2011 15:06

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.