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Identification
NameDiflunisal
Accession NumberDB00861  (APRD00922, DB06895)
Typesmall molecule
Groupsapproved
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
Synonyms
SynonymLanguageCode
DiflunisalGermanINN
DiflunisalFrenchINN
DiflunisalSpanishINN
DiflunisalumLatinINN
SaltsNot Available
Brand names
NameCompany
AntonEverest
DolobidMerck
Brand mixturesNot Available
CategoriesNot Available
CAS number22494-42-4
WeightAverage: 250.1976
Monoisotopic: 250.044150532
Chemical FormulaC13H8F2O3
InChI KeyInChIKey=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)
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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassBiphenyls and Derivatives
Direct parentBiphenyls and Derivatives
Alternative parentsSalicylic Acids; Benzoic Acids; Benzoyl Derivatives; Phenols and Derivatives; Fluorobenzenes; Aryl Fluorides; Enolates; Carboxylic Acids; Polyamines; Enols; Organofluorides
Substituentshydroxybenzoic acid; salicylic acid; salicylic acid or derivative; benzoic acid; benzoic acid or derivative; benzoyl; phenol derivative; fluorobenzene; aryl halide; aryl fluoride; enol; carboxylic acid; carboxylic acid derivative; polyamine; enolate; organohalogen; organofluoride
Classification descriptionThis compound belongs to the biphenyls and derivatives. These are organic compounds containing to benzene rings linked together by a C-C bond.
Pharmacology
IndicationFor symptomatic treatment of mild to moderate pain accompanied by inflammation (e.g. musculoskeletal trauma, post-dental extraction, post-episiotomy), osteoarthritis, and rheumatoid arthritis.
PharmacodynamicsDiflunisal 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 actionThe 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.
AbsorptionRapidly 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 distributionNot Available
Protein bindingAt least 98 to 99% of diflunisal in plasma is bound to proteins.
Metabolism

Hepatic, primarily via glucuronide conjugation (90% of administered dose).

Route of eliminationThe 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 life8 to 12 hours
ClearanceNot Available
ToxicityOral 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
PathwayCategorySMPDB ID
Diflunisal Action PathwayDrug actionSMP00289
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9945
Blood Brain Barrier + 0.8047
Caco-2 permeable + 0.8866
P-glycoprotein substrate Non-substrate 0.6927
P-glycoprotein inhibitor I Non-inhibitor 0.9407
P-glycoprotein inhibitor II Non-inhibitor 0.9735
Renal organic cation transporter Non-inhibitor 0.911
CYP450 2C9 substrate Non-substrate 0.7982
CYP450 2D6 substrate Non-substrate 0.9201
CYP450 3A4 substrate Non-substrate 0.7145
CYP450 1A2 substrate Non-inhibitor 0.9046
CYP450 2C9 substrate Inhibitor 0.6684
CYP450 2D6 substrate Non-inhibitor 0.9357
CYP450 2C19 substrate Non-inhibitor 0.9025
CYP450 3A4 substrate Non-inhibitor 0.8309
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.5156
Ames test Non AMES toxic 0.9666
Carcinogenicity Non-carcinogens 0.7828
Biodegradation Not ready biodegradable 0.988
Rat acute toxicity 2.7735 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.983
hERG inhibition (predictor II) Non-inhibitor 0.9178
Pharmacoeconomics
Manufacturers
  • Purepac pharmaceutical co
  • Roxane laboratories inc
  • Sandoz inc
  • Teva pharmaceuticals usa inc
  • Watson laboratories inc
  • Merck and co inc
Packagers
Dosage forms
FormRouteStrength
Tablet, film coatedOral250 mg
Tablet, film coatedOral500 mg
Prices
Unit descriptionCostUnit
Dolobid 60 500 mg tablet Bottle92.83USDbottle
Diflunisal 250 mg tablet1.74USDtablet
Diflunisal powder1.56USDg
Diflunisal 500 mg tablet1.46USDtablet
Apo-Diflunisal 500 mg Tablet0.75USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point210-221 °CPhysProp
water solubilityPractically insoluble (14.5 mg/L) at neutral or acidic pH.Not Available
logP4.44SANGSTER (1993)
Predicted Properties
PropertyValueSource
water solubility7.11e-02 g/lALOGPS
logP3.11ALOGPS
logP3.91ChemAxon
logS-3.5ALOGPS
pKa (strongest acidic)2.69ChemAxon
pKa (strongest basic)-6.3ChemAxon
physiological charge-1ChemAxon
hydrogen acceptor count3ChemAxon
hydrogen donor count2ChemAxon
polar surface area57.53ChemAxon
rotatable bond count2ChemAxon
refractivity60.86ChemAxon
polarizability22.29ChemAxon
number of rings2ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD00130
KEGG CompoundC01691
PubChem Compound3059
PubChem Substance46507807
ChemSpider2951
ChEBI39669
ChEMBLCHEMBL898
Therapeutic Targets DatabaseDAP000152
PharmGKBPA449313
HETFHI
Drug Product Database2058413
RxListhttp://www.rxlist.com/cgi/generic3/diflunisal.htm
Drugs.comhttp://www.drugs.com/cdi/diflunisal.html
PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/dol1145.shtml
WikipediaDiflunisal
ATC CodesN02BA11
AHFS Codes
  • 28:08.04.92
PDB EntriesNot Available
FDA labelshow(94.1 KB)
MSDSshow(73.4 KB)
Interactions
Drug Interactions
Drug
AcenocoumarolThe NSAID, diflunisal, may increase the anticoagulant effect of acenocoumarol.
AlendronateIncreased risk of gastric toxicity
AnisindioneThe NSAID, diflunisal, may increase the anticoagulant effect of anisindione.
Azilsartan medoxomilIncreases toxicity of each. May deteriorate renal function, particularly in volume depleted or elderly patients. Decreases effects of azilsartan by antagonism.
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.
DicoumarolThe NSAID, diflunisal, may increase the anticoagulant effect of dicumarol.
EltrombopagEltrombopag increases levels of Diflunisal via metabolism decrease.
Ginkgo bilobaAdditive anticoagulant/antiplatelet effects may increase bleed risk. Concomitant therapy should be avoided.
IndomethacinConcomitant therapy with the two NSAIDs, indomethacin and diflunisal, increases the risk of NSAID-related adverse effects (e.g. GI ulcers, bleeds, increased blood pressure).
LithiumThe NSAID, diflunisal, may decrease the renal excretion of lithium. Increased risk of lithium toxicity.
MethotrexateThe NSAID, diflunisal, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.
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 toxicity of diflunisal
TelmisartanConcomitant use of Telmisartan and Diflunisal may increase the risk of acute renal failure and hyperkalemia. Monitor renal function at the beginning and during treatment.
TimololThe NSAID, Diflunisal, may antagonize the antihypertensive effect of Timolol.
TrandolaprilThe 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.
TreprostinilThe prostacyclin analogue, Treprostinil, may increase the risk of bleeding when combined with the NSAID, Diflunisal. Monitor for increased bleeding during concomitant thearpy.
WarfarinThe 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.

1. 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. 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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

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

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

1. UDP-glucuronosyltransferase 1-8

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 1-8 Q9HAW9 Details

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

1. Transthyretin

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Transthyretin P02766 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Serum albumin P02768 Details

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

1. 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. 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

Comments
Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:12