U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ACHIRAL
Molecular Formula C13H8F2O3
Molecular Weight 250.1981
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of DIFLUNISAL

SMILES

c1cc(c(cc1-c2ccc(cc2F)F)C(=O)O)O

InChI

InChIKey=HUPFGZXOMWLGNK-UHFFFAOYSA-N
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)

HIDE SMILES / InChI

Molecular Formula C13H8F2O3
Molecular Weight 250.1981
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Diflunisal is a salicylic acid derivative with analgesic and anti-inflammatory activity. It was developed by Merck Sharp & Dohme in 1971 after showing promise in a research project studying more potent chemical analogs of aspirin. Diflunisal is an aspirin-like nonsteroidal anti-inflammatory drug that inhibits cyclooxygenase-2 (COX-2), an enzyme involved in prostaglandin synthesis.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.

CNS Activity

Curator's Comment:: Studies in baboons to determine passage across the blood-brain barrier have shown that only small quantities of diflunisal, under normal or acidotic conditions are transported into the cerebrospinal fluid (CSF). The ratio of blood/CSF concentrations after intravenous doses of 50 mg/kg or oral doses of 100 mg/kg of diflunisal was 100:1. In contrast, oral doses of 500 mg/kg of aspirin resulted in a blood/CSF ratio of 5:1.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
DOLOBID

Approved Use

Carefully consider the potential benefits and risks of diflunisal tablets and other treatment options before deciding to use diflunisal tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). Diflunisal tablets are indicated for acute or long-term use for symptomatic treatment of the following: Mild to moderate pain Osteoarthritis Rheumatoid arthritis

Launch Date

3.88022403E11
Primary
DOLOBID

Approved Use

Carefully consider the potential benefits and risks of diflunisal tablets and other treatment options before deciding to use diflunisal tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). Diflunisal tablets are indicated for acute or long-term use for symptomatic treatment of the following: Mild to moderate pain Osteoarthritis Rheumatoid arthritis

Launch Date

3.88022403E11
Primary
DOLOBID

Approved Use

Carefully consider the potential benefits and risks of diflunisal tablets and other treatment options before deciding to use diflunisal tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). Diflunisal tablets are indicated for acute or long-term use for symptomatic treatment of the following: Mild to moderate pain Osteoarthritis Rheumatoid arthritis

Launch Date

3.88022403E11
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
150 μg/mL
500 mg 2 times / day steady-state, oral
dose: 500 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
DIFLUNISAL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
186 μg/mL
100 mg 1 times / day steady-state, oral
dose: 100 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
DIFLUNISAL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
173.66 mg/L
500 mg single, oral
dose: 500 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
DIFLUNISAL plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
2782 μg × h/mL
500 mg 2 times / day steady-state, oral
dose: 500 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
DIFLUNISAL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
2839 μg × h/mL
100 mg 1 times / day steady-state, oral
dose: 100 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
DIFLUNISAL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
678 μg × h/mL
500 mg single, oral
dose: 500 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
DIFLUNISAL plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
11.4 h
500 mg single, oral
dose: 500 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
DIFLUNISAL plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: FASTED
Doses

Doses

DosePopulationAdverse events​
1500 mg 1 times / day steady, oral
Highest studied dose
Dose: 1500 mg, 1 times / day
Route: oral
Route: steady
Dose: 1500 mg, 1 times / day
Co-administed with::
indometacin(100 mg single-dose rectally)
Sources:
healthy, 35 years
n = 8
Health Status: healthy
Age Group: 35 years
Sex: M+F
Population Size: 8
Sources:
500 mg 1 times / day steady, oral
Dose: 500 mg, 1 times / day
Route: oral
Route: steady
Dose: 500 mg, 1 times / day
Sources:
unhealthy, 60.7 years (range: 25 - 80 years)
n = 40
Health Status: unhealthy
Condition: Hereditary ATTR amyloidosis
Age Group: 60.7 years (range: 25 - 80 years)
Sex: M+F
Population Size: 40
Sources:
Disc. AE: Impaired renal function, Thrombocytopenia...
AEs leading to
discontinuation/dose reduction:
Impaired renal function (2 patients)
Thrombocytopenia (1 patient)
Sources:
AEs

AEs

AESignificanceDosePopulation
Thrombocytopenia 1 patient
Disc. AE
500 mg 1 times / day steady, oral
Dose: 500 mg, 1 times / day
Route: oral
Route: steady
Dose: 500 mg, 1 times / day
Sources:
unhealthy, 60.7 years (range: 25 - 80 years)
n = 40
Health Status: unhealthy
Condition: Hereditary ATTR amyloidosis
Age Group: 60.7 years (range: 25 - 80 years)
Sex: M+F
Population Size: 40
Sources:
Impaired renal function 2 patients
Disc. AE
500 mg 1 times / day steady, oral
Dose: 500 mg, 1 times / day
Route: oral
Route: steady
Dose: 500 mg, 1 times / day
Sources:
unhealthy, 60.7 years (range: 25 - 80 years)
n = 40
Health Status: unhealthy
Condition: Hereditary ATTR amyloidosis
Age Group: 60.7 years (range: 25 - 80 years)
Sex: M+F
Population Size: 40
Sources:
Overview

Overview

CYP3A4CYP2C9CYP2D6hERG

OverviewOther

Drug as perpetrator​Drug as victim
PubMed

PubMed

TitleDatePubMed
Preparation of solid dispersions of nonsteroidal anti-inflammatory drugs with acrylic polymers and studies on mechanisms of drug-polymer interactions.
2002
An improved resazurin-based cytotoxicity assay for hepatic cells.
2002
Solid dispersions of diflunisal-PVP: polymorphic and amorphous states of the drug.
2002 Jul
Physicochemical properties of amorphous salt of cimetidine and diflunisal system.
2002 Jul 25
Self-association and cyclodextrin solubilization of drugs.
2002 Nov
Thermodynamics of solutions. II. Flurbiprofen and diflunisal as models for studying solvation of drug substances.
2003 Aug
Method development and validation for the analysis of meloxicam in tablets by CZE.
2003 Feb 26
Synthesis and biological activities of diflunisal hydrazide-hydrazones.
2003 Nov-Dec
Effect of vehicle pretreatment on the flux, retention, and diffusion of topically applied penetrants in vitro.
2003 Sep
Utilization of animal studies to determine the effects and human risks of environmental toxicants (drugs, chemicals, and physical agents).
2004 Apr
Diflunisal analogues stabilize the native state of transthyretin. Potent inhibition of amyloidogenesis.
2004 Jan 15
Drug delivery devices based on mesoporous silicate.
2004 Jan-Feb
Selective binding to transthyretin and tetramer stabilization in serum from patients with familial amyloidotic polyneuropathy by an iodinated diflunisal derivative.
2004 Jul 15
Gastrointestinally distributed UDP-glucuronosyltransferase 1A10, which metabolizes estrogens and nonsteroidal anti-inflammatory drugs, depends upon phosphorylation.
2004 Jul 2
Inverse gene expression patterns for macrophage activating hepatotoxicants and peroxisome proliferators in rat liver.
2004 Jun 1
Thermodynamics of solutions III: comparison of the solvation of (+)-naproxen with other NSAIDs.
2004 Mar
Compounds exhibiting selective efficacy for different beta subunits of human recombinant gamma-aminobutyric acid A receptors.
2004 Nov
Photosensitizing effect of some nonsteroidal antiinflammatory drugs on natural and artificial membranes: dependence on phospholipid composition.
2005 Feb
Radical cross-linked albumin microspheres as potential drug delivery systems: preparation and in vitro studies.
2005 Jul-Aug
Prediction of genotoxicity of chemical compounds by statistical learning methods.
2005 Jun
Human transthyretin in complex with iododiflunisal: structural features associated with a potent amyloid inhibitor.
2005 Jun 1
Dendrimers as potential drug carriers. Part I. Solubilization of non-steroidal anti-inflammatory drugs in the presence of polyamidoamine dendrimers.
2005 Nov
Role of monocarboxylic acid transporters in the cellular uptake of NSAIDs.
2005 Sep
pH-sensitive hydrogels based on bovine serum albumin for oral drug delivery.
2006 Apr 7
Orally administered diflunisal stabilizes transthyretin against dissociation required for amyloidogenesis.
2006 Dec
Diflunisal stabilizes familial amyloid polyneuropathy-associated transthyretin variant tetramers in serum against dissociation required for amyloidogenesis.
2006 Dec
Prediction of plasma protein binding displacement and its implications for quantitative assessment of metabolic drug-drug interactions from in vitro data.
2006 Dec
Allosteric modulation of [3H]EBOB binding to GABAA receptors by diflunisal analogues.
2006 Dec
Pharmaceutical quality control of acid and neutral drugs based on competitive self-assembly in amphiphilic systems.
2006 Jan
In vitro inhibitory effects of non-steroidal anti-inflammatory drugs on 4-methylumbelliferone glucuronidation in recombinant human UDP-glucuronosyltransferase 1A9--potent inhibition by niflumic acid.
2006 Jan
Drug Insight: emerging therapies for amyloidosis.
2006 May
Cell based screening of inhibitors of transthyretin aggregation.
2006 Sep 29
Comparison of inhibition potentials of drugs against zidovudine glucuronidation in rat hepatocytes and liver microsomes.
2007 Apr
Pre-emptive analgesia for removal of nasal packing: A double-blind placebo controlled study.
2007 Dec
Inhibitory potential of nonsteroidal anti-inflammatory drugs on UDP-glucuronosyltransferase 2B7 in human liver microsomes.
2007 Feb
A comparison of pre-emptive analgesic efficacy of diflunisal and lornoxicam for postoperative pain management: a prospective, randomized, single-blind, crossover study.
2007 Feb
Direct determination of closely overlapping drug mixtures of diflunisal and salicylic acid in serum by means of derivative matrix isopotential synchronous fluorescence spectrometry.
2007 Jan 30
Synthesis of some novel heterocyclic compounds derived from diflunisal hydrazide as potential anti-infective and anti-inflammatory agents.
2007 Jul
FluSTAR, a novel influenza surveillance system: outcomes from the 2005-2006 flu season.
2007 Sep
100,000-fold concentration of anions in capillary zone electrophoresis using electroosmotic flow controlled counterflow isotachophoretic stacking under field amplified conditions.
2008 Aug 15
Molecular interactions in lipophilic environments studied by electrochemistry at interfaces between immiscible electrolyte solutions.
2008 Jan 1
Species differences in inhibition potential of nonsteroidal anti-inflammatory drugs against estradiol 3beta-glucuronidation between rats, dogs, and humans.
2008 Jul
The modulation of transthyretin tetramer stability by cysteine 10 adducts and the drug diflunisal. Direct analysis by fluorescence-detected analytical ultracentrifugation.
2008 May 2
Chemical substructures that enrich for biological activity.
2008 Nov 1
Chemometric assisted solid-phase microextraction for the determination of anti-inflammatory and antiepileptic drugs in river water by liquid chromatography-diode array detection.
2008 Nov 21
In vitro inhibition of salicylic acid derivatives on human cytosolic carbonic anhydrase isozymes I and II.
2008 Oct 15
Simultaneous determination of naproxen and diflunisal using synchronous luminescence spectrometry.
2008 Sep
Differential scanning calorimetry study on drug release from an inulin-based hydrogel and its interaction with a biomembrane model: pH and loading effect.
2008 Sep 2
Simultaneous determination of two anti-inflammatory drugs in serum using isopotential fluorimetry.
2008 Sep 5
Patents

Sample Use Guides

For mild to moderate pain, an initial dose of 1000 mg followed by 500 mg every 12 hours is recommended for most patients. Following the initial dose, some patients may require 500 mg every 8 hours. A lower dosage may be appropriate depending on such factors as pain severity, patient response, weight, or advanced age; for example, 500 mg initially, followed by 250 mg every 8-12 hours. For osteoarthritis and rheumatoid arthritis, the suggested dosage range is 500 mg to 1000 mg daily in two divided doses. The dosage of DOLOBID may be increased or decreased according to patient response. Maintenance doses higher than 1500 mg a day are not recommended.
Route of Administration: Oral
To a solution of human serum albumin (Sigma, 40 mg/mL in 50 mM phosphate buffered saline, pH 7.4), Diflunisal were added to a final concentration of 20 mkg/mL in 1 mL total volume. The mixtures were allowed to equilibrate for 1 h at room temperature and were then centrifuged at 86 000 x g for 18 h. The resulting gradient was fractionated into 5 x 200 mkL samples and extracted with acetonitrile in preparation for analysis by reverse-phase high-performance liquid chromatography. A mobile phase of 55:45 CH3CN/0.1% trifluoroacetic acid at a flow rate of 1 mL/min with a Luna C18 (100 x 4.6 mm) column and ultraviolet detection at 210 nm were used for compound detection. To calculate the fraction of free Diflunisal , the area of the chromatographic compound peak for the upper protein-free fraction was divided by the total peak area for the entire gradient.
Substance Class Chemical
Created
by admin
on Fri Jun 25 21:03:02 UTC 2021
Edited
by admin
on Fri Jun 25 21:03:02 UTC 2021
Record UNII
7C546U4DEN
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
DIFLUNISAL
EP   INN   JAN   MART.   MI   ORANGE BOOK   USAN   USP   USP-RS   VANDF   WHO-DD  
USAN   INN  
Official Name English
(1,1'-BIPHENYL)-3-CARBOXYLIC ACID, 2',4'-DIFLUORO-4-HYDROXY-
Common Name English
NSC-756728
Code English
DIFLUNISAL [ORANGE BOOK]
Common Name English
DIFLUNISAL [USP-RS]
Common Name English
DOLOBID
Brand Name English
DIFLUNISAL [MI]
Common Name English
DIFLUNISAL [JAN]
Common Name English
DIFLUNISAL [EP]
Common Name English
DIFLUNISAL [USP MONOGRAPH]
Common Name English
2',4'-DIFLUORO-4-HYDROXY-3-BIPHENYLCARBOXYLIC ACID
Systematic Name English
DIFLUNISAL [MART.]
Common Name English
DIFLUNISAL [INN]
Common Name English
DIFLUNISAL [USP]
Common Name English
DIFLUNISAL [VANDF]
Common Name English
DIFLUNISAL [USAN]
Common Name English
Classification Tree Code System Code
NDF-RT N0000175722
Created by admin on Fri Jun 25 21:03:02 UTC 2021 , Edited by admin on Fri Jun 25 21:03:02 UTC 2021
NCI_THESAURUS C257
Created by admin on Fri Jun 25 21:03:02 UTC 2021 , Edited by admin on Fri Jun 25 21:03:02 UTC 2021
NDF-RT N0000175721
Created by admin on Fri Jun 25 21:03:02 UTC 2021 , Edited by admin on Fri Jun 25 21:03:02 UTC 2021
LIVERTOX 305
Created by admin on Fri Jun 25 21:03:02 UTC 2021 , Edited by admin on Fri Jun 25 21:03:02 UTC 2021
NDF-RT N0000000160
Created by admin on Fri Jun 25 21:03:02 UTC 2021 , Edited by admin on Fri Jun 25 21:03:02 UTC 2021
WHO-ATC N02BA11
Created by admin on Fri Jun 25 21:03:02 UTC 2021 , Edited by admin on Fri Jun 25 21:03:02 UTC 2021
WHO-VATC QN02BA11
Created by admin on Fri Jun 25 21:03:02 UTC 2021 , Edited by admin on Fri Jun 25 21:03:02 UTC 2021
Code System Code Type Description
DRUG CENTRAL
880
Created by admin on Fri Jun 25 21:03:02 UTC 2021 , Edited by admin on Fri Jun 25 21:03:02 UTC 2021
PRIMARY
ChEMBL
CHEMBL898
Created by admin on Fri Jun 25 21:03:02 UTC 2021 , Edited by admin on Fri Jun 25 21:03:02 UTC 2021
PRIMARY
EPA CompTox
22494-42-4
Created by admin on Fri Jun 25 21:03:02 UTC 2021 , Edited by admin on Fri Jun 25 21:03:02 UTC 2021
PRIMARY
FDA UNII
7C546U4DEN
Created by admin on Fri Jun 25 21:03:02 UTC 2021 , Edited by admin on Fri Jun 25 21:03:02 UTC 2021
PRIMARY
WIKIPEDIA
DIFLUNISAL
Created by admin on Fri Jun 25 21:03:02 UTC 2021 , Edited by admin on Fri Jun 25 21:03:02 UTC 2021
PRIMARY
MERCK INDEX
M4435
Created by admin on Fri Jun 25 21:03:02 UTC 2021 , Edited by admin on Fri Jun 25 21:03:02 UTC 2021
PRIMARY Merck Index
ECHA (EC/EINECS)
245-034-9
Created by admin on Fri Jun 25 21:03:02 UTC 2021 , Edited by admin on Fri Jun 25 21:03:02 UTC 2021
PRIMARY
EVMPD
SUB07130MIG
Created by admin on Fri Jun 25 21:03:02 UTC 2021 , Edited by admin on Fri Jun 25 21:03:02 UTC 2021
PRIMARY
NCI_THESAURUS
C47489
Created by admin on Fri Jun 25 21:03:02 UTC 2021 , Edited by admin on Fri Jun 25 21:03:02 UTC 2021
PRIMARY
RXCUI
3393
Created by admin on Fri Jun 25 21:03:02 UTC 2021 , Edited by admin on Fri Jun 25 21:03:02 UTC 2021
PRIMARY RxNorm
CAS
22494-42-4
Created by admin on Fri Jun 25 21:03:02 UTC 2021 , Edited by admin on Fri Jun 25 21:03:02 UTC 2021
PRIMARY
LACTMED
Diflunisal
Created by admin on Fri Jun 25 21:03:02 UTC 2021 , Edited by admin on Fri Jun 25 21:03:02 UTC 2021
PRIMARY
MESH
D004061
Created by admin on Fri Jun 25 21:03:02 UTC 2021 , Edited by admin on Fri Jun 25 21:03:02 UTC 2021
PRIMARY
INN
3774
Created by admin on Fri Jun 25 21:03:02 UTC 2021 , Edited by admin on Fri Jun 25 21:03:02 UTC 2021
PRIMARY
USP_CATALOG
1197506
Created by admin on Fri Jun 25 21:03:02 UTC 2021 , Edited by admin on Fri Jun 25 21:03:02 UTC 2021
PRIMARY USP-RS
PUBCHEM
3059
Created by admin on Fri Jun 25 21:03:02 UTC 2021 , Edited by admin on Fri Jun 25 21:03:02 UTC 2021
PRIMARY
IUPHAR
7162
Created by admin on Fri Jun 25 21:03:02 UTC 2021 , Edited by admin on Fri Jun 25 21:03:02 UTC 2021
PRIMARY
DRUG BANK
DB00861
Created by admin on Fri Jun 25 21:03:02 UTC 2021 , Edited by admin on Fri Jun 25 21:03:02 UTC 2021
PRIMARY
Related Record Type Details
SALT/SOLVATE -> PARENT
TRANSPORTER -> INHIBITOR
DEGRADENT -> PARENT
Related Record Type Details
ACTIVE MOIETY