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Identification
Name Diflunisal
Accession Number DB00861 (APRD00922, DB06895)
Type small molecule
Groups approved
Description

Diflunisal, a salicylate derivative, is a nonsteroidal anti-inflammatory agent (NSAIA) with pharmacologic actions similar to other prototypical NSAIAs. Diflunisal possesses anti-inflammatory, analgesic and antipyretic activity. Though its mechanism of action has not been clearly established, most of its actions appear to be associated with inhibition of prostaglandin synthesis via the arachidonic acid pathway. Diflunisal is used to relieve pain accompanied with inflammation and in the symptomatic treatment of rheumatoid arthritis and osteoarthritis.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms Not Available
Salts Not Available
Brand names
Name Company
Adomal
Difludol
Dolisal
Dolobid Merck
Dolobil
Dolobis
Flovacil
Fluniget
Fluodonil
Flustar
Brand mixtures Not Available
Categories
  • Anti-inflammatory Agents
  • Cyclooxygenase Inhibitors
  • Analgesics
  • Analgesics, Non-Narcotic
  • Antipyretics
  • Nonsteroidal Anti-inflammatory Agents (NSAIAs)
CAS number 22494-42-4
Weight Average: 250.1976
Monoisotopic: 250.044150532
Chemical Formula C13H8F2O3
InChI Key InChIKey=HUPFGZXOMWLGNK-UHFFFAOYSA-N
InChI
InChI=1S/C13H8F2O3/c14-8-2-3-9(11(15)6-8)7-1-4-12(16)10(5-7)13(17)18/h1-6,16H,(H,17,18)
Plain Text
IUPAC Name
5-(2,4-difluorophenyl)-2-hydroxybenzoic acid
SMILES
OC(=O)C1=C(O)C=CC(=C1)C1=C(F)C=C(F)C=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Biphenyl and Derivatives
Substructures
  • Hydroxy Compounds
  • Benzyl Alcohols and Derivatives
  • Acetates
  • Benzoates
  • Salicylates and Derivatives
  • Phenols and Derivatives
  • Benzene and Derivatives
  • Biphenyl and Derivatives
  • Carboxylic Acids and Derivatives
  • Halobenzenes
  • Aromatic compounds
  • Benzoyl Derivatives
  • Aryl Halides
  • Phenyl Esters
Pharmacology
Indication For symptomatic treatment of mild to moderate pain accompanied by inflammation (e.g. musculoskeletal trauma, post-dental extraction, post-episiotomy), osteoarthritis, and rheumatoid arthritis.
Pharmacodynamics Diflunisal is a nonsteroidal drug with analgesic, anti-inflammatory and antipyretic properties. It is a peripherally-acting non-narcotic analgesic drug. Habituation, tolerance and addiction have not been reported. Diflunisal is a difluorophenyl derivative of salicylic acid. Chemically, diflunisal differs from aspirin (acetylsalicylic acid) in two respects. The first of these two is the presence of a difluorophenyl substituent at carbon 1. The second difference is the removal of the 0-acetyl group from the carbon 4 position. Diflunisal is not metabolized to salicylic acid, and the fluorine atoms are not displaced from the difluorophenyl ring structure.
Mechanism of action The precise mechanism of the analgesic and anti-inflammatory actions of diflunisal is not known. Diflunisal is a prostaglandin synthetase inhibitor. In animals, prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain. Since prostaglandins are known to be among the mediators of pain and inflammation, the mode of action of diflunisal may be due to a decrease of prostaglandins in peripheral tissues.
Absorption Rapidly and completely absorbed following oral administration, with a bioavailability of 80-90%. Peak plasma concentrations are achieved 2 - 3 hours following oral administration.
Volume of distribution Not Available
Protein binding At least 98 to 99% of diflunisal in plasma is bound to proteins.
Metabolism Hepatic, primarily via glucuronide conjugation (90% of administered dose).
Route of elimination The drug is excreted in the urine as two soluble glucuronide conjugates accounting for about 90% of the administered dose. Little or no diflunisal is excreted in the feces.
Half life 8 to 12 hours
Clearance Not Available
Toxicity Oral LD50 in rat, mouse, and rabbit is 392 mg/kg, 439 mg/kg, and 603 mg/kg, respectively. Symptoms of overdose include drowsiness, nausea, vomiting, diarrhea, hyperventilation, tachycardia, sweating, tinnitus, disorientation, stupor, and coma. The lowest dose without the presence of other medicines which caused death was 15 grams.

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 diflunisal. Short-term use does not appear to be associated with increased cardiovascular risk (except when used immediately following coronary artery bypass graft (CABG) surgery). Risk of GI toxicity including bleeding, ulceration and perforation. Risk of direct renal injury, including renal papillary necrosis. Severe hepatic reactions, including cholestasis and/or jaundice, have been reported. May cause rash or hypersensitivity syndrome.
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00289 Diflunisal Pathway SMP00289
Pharmacoeconomics
Manufacturers
  • Purepac pharmaceutical co
  • Roxane laboratories inc
  • Sandoz inc
  • Teva pharmaceuticals usa inc
  • Watson laboratories inc
  • Merck and co inc
Packagers
Dosage forms
Form Route Strength
Tablet, film coated Oral 250 mg
Tablet, film coated Oral 500 mg
Prices
Unit description Cost Unit
Dolobid 60 500 mg tablet Bottle 92.83 USD bottle
Diflunisal 250 mg tablet 1.74 USD tablet
Diflunisal powder 1.56 USD g
Diflunisal 500 mg tablet 1.46 USD tablet
Apo-Diflunisal 500 mg Tablet 0.75 USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents Not Available
Properties
State solid
Experimental Properties
Property Value Source
melting point 210-221 °C PhysProp
water solubility Practically insoluble (14.5 mg/L) at neutral or acidic pH. Not Available
logP 4.44 SANGSTER (1993)
Predicted Properties
Property Value Source
water solubility 7.11e-02 g/l ALOGPS
logP 3.11 ALOGPS
logP 3.91 ChemAxon
logS -3.5 ALOGPS
pKa (strongest acidic) 2.69 ChemAxon
pKa (strongest basic) -6.3 ChemAxon
physiological charge -1 ChemAxon
hydrogen acceptor count 3 ChemAxon
hydrogen donor count 2 ChemAxon
polar surface area 57.53 ChemAxon
rotatable bond count 2 ChemAxon
refractivity 60.86 ChemAxon
polarizability 22.29 ChemAxon
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D00130 Link_out
KEGG Compound C01691 Link_out
PubChem Compound 3059 Link_out
PubChem Substance 46507807 Link_out
ChemSpider 2951 Link_out
ChEBI 39669 Link_out
ChEMBL 39669 Link_out
Therapeutic Targets Database DAP000152 Link_out
PharmGKB PA449313 Link_out
HET FHI Link_out
Drug Product Database 2058413 Link_out
RxList http://www.rxlist.com/cgi/generic3/diflunisal.htm Link_out
Drugs.com http://www.drugs.com/cdi/diflunisal.html Link_out
PDRhealth http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/dol1145.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Diflunisal Link_out
ATC Codes
  • N02BA11
AHFS Codes
  • 28:08.04.92
PDB Entries Not Available
FDA label show (94.1 KB)
MSDS show (73.4 KB)
Interactions
Drug Interactions
Drug Interaction
Acenocoumarol The NSAID, diflunisal, may increase the anticoagulant effect of acenocoumarol.
Alendronate Increased risk of gastric toxicity
Anisindione The NSAID, diflunisal, may increase the anticoagulant effect of anisindione.
Colesevelam Bile 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.
Dicumarol The NSAID, diflunisal, may increase the anticoagulant effect of dicumarol.
Eltrombopag Eltrombopag increases levels of Diflunisal via metabolism decrease.
Ginkgo biloba Additive anticoagulant/antiplatelet effects may increase bleed risk. Concomitant therapy should be avoided.
Indomethacin Concomitant therapy with the two NSAIDs, indomethacin and diflunisal, increases the risk of NSAID-related adverse effects (e.g. GI ulcers, bleeds, increased blood pressure).
Lithium The NSAID, diflunisal, may decrease the renal excretion of lithium. Increased risk of lithium toxicity.
Methotrexate The NSAID, diflunisal, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.
Pralatrexate NSAIDs 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.
Probenecid Probenecid increases toxicity of diflunisal
Telmisartan Concomitant use of Telmisartan and Diflunisal may increase the risk of acute renal failure and hyperkalemia. Monitor renal function at the beginning and during treatment.
Timolol The NSAID, Diflunisal, may antagonize the antihypertensive effect of Timolol.
Trandolapril The NSAID, Diflunisal, may reduce the antihypertensive effect of Trandolapril. Consider alternate therapy or monitor for changes in Trandolapril efficacy if Diflunisal is initiated, discontinued or dose changed.
Treprostinil The prostacyclin analogue, Treprostinil, may increase the risk of bleeding when combined with the NSAID, Diflunisal. Monitor for increased bleeding during concomitant thearpy.
Warfarin The antiplatelet effects of diflunisal may increase the bleed risk associated with warfarin. Consider alternate therapy or monitor for signs and symptoms of bleeding during concomitant therapy.
Food Interactions
  • Avoid alcohol.
  • Food slightly delays rate of absorption 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. Cappon GD, Cook JC, Hurtt ME: Relationship between cyclooxygenase 1 and 2 selective inhibitors and fetal development when administered to rats and rabbits during the sensitive periods for heart development and midline closure. Birth Defects Res B Dev Reprod Toxicol. 2003 Feb;68(1):47-56. Pubmed
  2. Jeske AH: COX-2 inhibitors and dental pain control. J Gt Houst Dent Soc. 1999 Nov;71(4):39-40. Pubmed
  3. Mao H, Hajduk PJ, Craig R, Bell R, Borre T, Fesik SW: Rational design of diflunisal analogues with reduced affinity for human serum albumin. J Am Chem Soc. 2001 Oct 31;123(43):10429-35. Pubmed
  4. Moore PA, Hersh EV: Celecoxib and rofecoxib. The role of COX-2 inhibitors in dental practice. J Am Dent Assoc. 2001 Apr;132(4):451-6. Pubmed
  5. Young JM, Panah S, Satchawatcharaphong C, Cheung PS: Human whole blood assays for inhibition of prostaglandin G/H synthases-1 and -2 using A23187 and lipopolysaccharide stimulation of thromboxane B2 production. Inflamm Res. 1996 May;45(5):246-53. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. 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. Cappon GD, Cook JC, Hurtt ME: Relationship between cyclooxygenase 1 and 2 selective inhibitors and fetal development when administered to rats and rabbits during the sensitive periods for heart development and midline closure. Birth Defects Res B Dev Reprod Toxicol. 2003 Feb;68(1):47-56. Pubmed
  2. Chen QH, Rao PN, Knaus EE: Design, synthesis, and biological evaluation of N-acetyl-2-carboxybenzenesulfonamides: a novel class of cyclooxygenase-2 (COX-2) inhibitors. Bioorg Med Chem. 2005 Apr 1;13(7):2459-68. Pubmed
  3. Young JM, Panah S, Satchawatcharaphong C, Cheung PS: Human whole blood assays for inhibition of prostaglandin G/H synthases-1 and -2 using A23187 and lipopolysaccharide stimulation of thromboxane B2 production. Inflamm Res. 1996 May;45(5):246-53. Pubmed
Enzymes

1. UDP-glucuronosyltransferase 1-8

Actions: substrate

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

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

References:
  1. Cheng Z, Radominska-Pandya A, Tephly TR: Studies on the substrate specificity of human intestinal UDP- lucuronosyltransferases 1A8 and 1A10. Drug Metab Dispos. 1999 Oct;27(10):1165-70. 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
  2. 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
Carriers

1. Transthyretin

Thyroid hormone-binding protein. Probably transports thyroxine from the bloodstream to the brain

UniProt ID: P02766 Link_out
Gene: TTR Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Adamski-Werner SL, Palaninathan SK, Sacchettini JC, Kelly JW: Diflunisal analogues stabilize the native state of transthyretin. Potent inhibition of amyloidogenesis. J Med Chem. 2004 Jan 15;47(2):355-74. Pubmed
  2. Almeida MR, Macedo B, Cardoso I, Alves I, Valencia G, Arsequell G, Planas A, Saraiva MJ: Selective binding to transthyretin and tetramer stabilization in serum from patients with familial amyloidotic polyneuropathy by an iodinated diflunisal derivative. Biochem J. 2004 Jul 15;381(Pt 2):351-6. Pubmed
  3. Gales L, Macedo-Ribeiro S, Arsequell G, Valencia G, Saraiva MJ, Damas AM: Human transthyretin in complex with iododiflunisal: structural features associated with a potent amyloid inhibitor. Biochem J. 2005 Jun 1;388(Pt 2):615-21. Pubmed
  4. Miller SR, Sekijima Y, Kelly JW: Native state stabilization by NSAIDs inhibits transthyretin amyloidogenesis from the most common familial disease variants. Lab Invest. 2004 May;84(5):545-52. Pubmed
  5. Tojo K, Sekijima Y, Kelly JW, Ikeda S: Diflunisal stabilizes familial amyloid polyneuropathy-associated transthyretin variant tetramers in serum against dissociation required for amyloidogenesis. Neurosci Res. 2006 Dec;56(4):441-9. Epub 2006 Oct 6. Pubmed

2. 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. Davilas A, Koupparis M, Macheras P, Valsami G: In-vitro study on the competitive binding of diflunisal and uraemic toxins to serum albumin and human plasma using a potentiometric ion-probe technique. J Pharm Pharmacol. 2006 Nov;58(11):1467-74. Pubmed
  2. Mao H, Hajduk PJ, Craig R, Bell R, Borre T, Fesik SW: Rational design of diflunisal analogues with reduced affinity for human serum albumin. J Am Chem Soc. 2001 Oct 31;123(43):10429-35. Pubmed
  3. Rehse K, Fiedler B: [Determination of the protein binding of drugs by continuous ultrafiltration. 9. Comparison of the binding of nonsteroid antirheumatics to human serum albumin and their interaction with phenprocoumon] Arch Pharm (Weinheim). 1989 Apr;322(4):241-3. Pubmed
  4. Verbeeck RK, De Schepper PJ: Influence of chronic renal failure and hemodialysis on diflunisal plasma protein binding. Clin Pharmacol Ther. 1980 May;27(5):628-35. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19