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Identification
Name Ketorolac
Accession Number DB00465 (APRD01060)
Type small molecule
Groups approved
Description

A pyrrolizine carboxylic acid derivative structurally related to indomethacin. It is an NSAID and is used principally for its analgesic activity. (From Martindale The Extra Pharmacopoeia, 31st ed)
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Ketoralac
  • Ketorolac Tromethamine
  • Ketorolaco [Spanish]
  • Ketorolacum [Latin]
Brand names
  • Acular
  • Acular LS
  • Acular Preservative Free
  • Toradol
Brand name mixtures Not Available
Categories
  • Cyclooxygenase Inhibitors
CAS number 66635-83-4
Weight Average: 255.2686
Monoisotopic: 255.089543287
Chemical Formula C15H13NO3
InChI Key InChIKey=OZWKMVRBQXNZKK-UHFFFAOYSA-N
InChI
InChI=1S/C15H13NO3/c17-14(10-4-2-1-3-5-10)13-7-6-12-11(15(18)19)8-9-16(12)13/h1-7,11H,8-9H2,(H,18,19)
Plain Text
IUPAC Name
5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid
SMILES
OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Pyrrolizines
  • Benzoyl Derivatives
Substructures
  • Hydroxy Compounds
  • Acetates
  • Carboxylic Acids and Derivatives
  • Pyrroles
  • Benzene and Derivatives
  • Pyrrolizines
  • Heterocyclic compounds
  • Aromatic compounds
  • Imines
  • Benzoyl Derivatives
  • Pyrrolines
  • Ketones
Pharmacology
Indication For the short-term (~5 days) management of moderately severe acute pain that requires analgesia at the opioid level, usually in a postoperative setting.
Pharmacodynamics Ketorolac, an antiinflammatory agent with analgesic and antipyretic properties, is used to treat osteoarthritis and control acute pain. It is a peripherally acting analgesic. The biological activity of ketorolac tromethamine is associated with the S-form. Ketorolac tromethamine possesses no sedative or anxiolytic properties.
Mechanism of action Ketorolac is a nonsteroidal anti-inflammatory drug (NSAID) chemically related to indomethacin and tolmetin. Ketorolac tromethamine is a racemic mixture of [-]S- and [+]R-enantiomeric forms, with the S-form having analgesic activity. Its antiinflammatory effects are believed to be due to inhibition of both cylooxygenase-1 (COX-1) and cylooxygenase-2 (COX-2) which leads to the inhibition of prostaglandin synthesis leading to decreased formation of precursors of prostaglandins and thromboxanes from arachidonic acid. The resultant reduction in prostaglandin synthesis and activity may be at least partially responsible for many of the adverse, as well as the therapeutic, effects of these medications. Analgesia is probably produced via a peripheral action in which blockade of pain impulse generation results from decreased prostaglandin activity. However, inhibition of the synthesis or actions of other substances that sensitize pain receptors to mechanical or chemical stimulation may also contribute to the analgesic effect. In terms of the ophthalmic applications of ketorolac - ocular administration of ketorolac reduces prostaglandin E2 levels in aqueous humor, secondary to inhibition of prostaglandin biosynthesis.
Absorption Rapidly and completely absorbed after oral administration
Volume of distribution
  • 0.26 ± 0.08 L/kg [children 4 to 8 years old]
Protein binding 99%
Metabolism

Primarily hepatic. Less than 50% of a dose is metabolized. The major metabolites are a glucuronide conjugate, which may also be formed in the kidney, and p-hydroxy ketorolac. Neither metabolite has significant analgesic activity.
Route of elimination The principal route of elimination of ketorolac and its metabolites is renal. Approximately 6% of a dose is excreted in the feces.
Half life 2.5 hours for the S-enantiomer compared with 5 hours for the R-enantiomer
Clearance
  • 0.042 +/- 0.01 L/hr/kg [Pediatric Patients]
  • 0.02 L/h/kg [Normal Subjects IM]
  • 0.03 L/h/kg [Normal Subjects oral]
  • 0.02 L/h/kg [Healthy Elderly Subjects IM]
  • 0.02 L/h/kg [Healthy Elderly Subjects oral]
  • 0.03 L/h/kg [Patients with Hepatic Dysfunction IM]
  • 0.03 L/h/kg [Patients with Hepatic Dysfunction oral]
  • 0.02 L/h/kg [Patients with Renal Impairment IM]
  • 0.02 L/h/kg [Patients with Renal Impairment oral]
  • 0.02 L/h/kg [Renal Dialysis Patients IM]
Toxicity LD50 = 189 mg/kg (rat, oral).
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00098 Ketorolac Pathway SMP00098
Pharmacoeconomics
Manufacturers
  • Akorn strides llc
  • Amphastar pharmaceutical inc
  • Apotex inc richmond hill
  • Apothecon inc div bristol myers squibb
  • App pharmaceuticals llc
  • Baxter healthcare corp anesthesia and critical care
  • Baxter healthcare corp anesthesia critical care
  • Bedford laboratories div ben venue laboratories inc
  • Claris lifesciences ltd
  • Gland pharma ltd
  • Hospira inc
  • Luitpold pharmaceuticals inc
  • Sandoz canada inc
  • Sun pharma global inc
  • Wockhardt ltd
  • Roche palo alto llc
  • Allergan inc
  • Allergan
  • Akorn inc
  • Alcon inc
  • Roxro pharma inc
  • Mylan pharmaceuticals inc
  • Pliva inc
  • Roxane laboratories inc
  • Teva pharmaceuticals usa inc
  • Watson laboratories inc
Packagers
Dosage forms
Form Route Strength
Liquid Intramuscular
Solution Intramuscular
Solution Ophthalmic
Tablet Oral
Prices
Unit description Cost Unit
Acular 0.5% Solution 10ml Bottle 254.39 USD bottle
Acular 0.5% Solution 5ml Bottle 122.36 USD bottle
Ketorolac Tromethamine 0.4% Solution 5ml Bottle 109.72 USD bottle
Ketorolac tromethamine powder 71.05 USD g
Acular 0.5% Solution 3ml Bottle 59.34 USD bottle
Acular ls 0.4% ophth sol 24.46 USD ml
Acular 0.5% eye drops 18.68 USD ml
Ketorolac 30 mg/ml syringe 8.77 USD ml
Ketorolac 15 mg/ml syringe 8.39 USD ml
Acuvail 0.45% ophth solution 4.17 USD each
Ketorolac Tromethamine 30 mg/ml 3.9 USD ml
Acular 0.5 % Solution 3.78 USD ml
Toradol 10 mg/ml 2.52 USD ml
Ketorolac im 30 mg/ml syring 2.11 USD ml
Apo-Ketorolac 0.5 % Solution 2.11 USD ml
Ratio-Ketorolac 0.5 % Solution 2.11 USD ml
Toradol 10 mg tablet 1.53 USD tablet
Ketorolac Tromethamine 10 mg tablet 1.06 USD tablet
Ketorolac 10 mg tablet 0.93 USD tablet
Toradol 10 mg Tablet 0.76 USD tablet
Apo-Ketorolac 10 mg Tablet 0.43 USD tablet
Novo-Ketorolac 10 mg Tablet 0.43 USD tablet
Nu-Ketorolac 10 mg Tablet 0.43 USD tablet
Patents
Country Patent Number Approved Expires
United States 6333044 1998-12-25 2018-12-25
United States 5110493 1992-11-05 2009-11-05
Canada 1328614 1994-04-19 2011-04-19
Properties
State solid
Melting point 165-167 oC (tromethamine salt)
Experimental Properties
Property Value Source
water solubility 25 mg/mL (tromethamine salt) PhysProp
logP 2.1 PhysProp
Predicted Properties
Property Value Source
water solubility 5.13e-01 g/l ALOGPS
logP 2.66 ALOGPS
logP 2.28 ChemAxon Molconvert
logS -2.70 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 3 ChemAxon Molconvert
hydrogen donor count 1 ChemAxon Molconvert
polar surface area 59.30 ChemAxon Molconvert
rotatable bond count 3 ChemAxon Molconvert
refractivity 70.19 ChemAxon Molconvert
polarizability 26.67 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Compound C07062 Link_out
PubChem Compound 3826 Link_out
PubChem Substance 46507019 Link_out
ChemSpider 3694 Link_out
BindingDB 50009855 Link_out
Therapeutic Targets Database DAP000618 Link_out
PharmGKB PA450150 Link_out
Drug Product Database 2239944 Link_out
RxList http://www.rxlist.com/cgi/generic/ketor.htm Link_out
Drugs.com http://www.drugs.com/cdi/ketorolac-drops.html Link_out
PDRhealth http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/acu1644.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Ketorolac Link_out
ATC Codes
  • M01AB15
  • S01BC05
AHFS Codes
  • 28:08.04.92
  • 52:08.20
PDB Entries Not Available
FDA label show (137.6 KB)
MSDS show (76.4 KB)
Interactions
Drug Interactions Not Available
Food Interactions
  • Take with food to reduce GI 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. Hocherl K, Kammerl MC, Schumacher K, Endemann D, Grobecker HF, Kurtz A: Role of prostanoids in regulation of the renin-angiotensin-aldosterone system by salt intake. Am J Physiol Renal Physiol. 2002 Aug;283(2):F294-301. Pubmed
  2. Blais V, Zhang J, Rivest S: In altering the release of glucocorticoids, ketorolac exacerbates the effects of systemic immune stimuli on expression of proinflammatory genes in the brain. Endocrinology. 2002 Dec;143(12):4820-7. Pubmed
  3. Ma W, Eisenach JC: Intraplantar injection of a cyclooxygenase inhibitor ketorolac reduces immunoreactivities of substance P, calcitonin gene-related peptide, and dynorphin in the dorsal horn of rats with nerve injury or inflammation. Neuroscience. 2003;121(3):681-90. Pubmed
  4. Ma W, Eisenach JC: Cyclooxygenase 2 in infiltrating inflammatory cells in injured nerve is universally up-regulated following various types of peripheral nerve injury. Neuroscience. 2003;121(3):691-704. Pubmed
  5. Padi SS, Jain NK, Singh S, Kulkarni SK: Pharmacological profile of parecoxib: a novel, potent injectable selective cyclooxygenase-2 inhibitor. Eur J Pharmacol. 2004 Apr 26;491(1):69-76. 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. Bosch-Marce M, Claria J, Titos E, Masferrer JL, Altuna R, Poo JL, Jimenez W, Arroyo V, Rivera F, Rodes J: Selective inhibition of cyclooxygenase 2 spares renal function and prostaglandin synthesis in cirrhotic rats with ascites. Gastroenterology. 1999 May;116(5):1167-75. Pubmed
  2. Lashbrook JM, Ossipov MH, Hunter JC, Raffa RB, Tallarida RJ, Porreca F: Synergistic antiallodynic effects of spinal morphine with ketorolac and selective COX1- and COX2-inhibitors in nerve-injured rats. Pain. 1999 Jul;82(1):65-72. Pubmed
  3. Dionne RA, Khan AA, Gordon SM: Analgesia and COX-2 inhibition. Clin Exp Rheumatol. 2001 Nov-Dec;19(6 Suppl 25):S63-70. Pubmed
  4. Uzan A: The unexpected side effects of new nonsteroidal anti-inflammatory drugs. Expert Opin Emerg Drugs. 2005 Nov;10(4):687-8. Pubmed
  5. Blais V, Turrin NP, Rivest S: Cyclooxygenase 2 (COX-2) inhibition increases the inflammatory response in the brain during systemic immune stimuli. J Neurochem. 2005 Dec;95(6):1563-74. Epub 2005 Nov 8. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on November 10, 2010 13:39

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.