DIFLUNISAL

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 Search

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

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018445s058lbl.pdf

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

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Cyclooxygenase-2 189 Target ID: CHEMBL230 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11673972	Inhibitor 7728

Conditions

Condition	Modality	Highest Phase	Product
Pain 580 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018445s058lbl.pdf	Primary	Approved 8043	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
Osteoarthritis 151 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018445s058lbl.pdf	Primary	Approved 8043	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
Rheumatoid arthritis 294 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018445s058lbl.pdf	Primary	Approved 8043	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

C_max

Value	Dose	Analyte	Population
150 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/3841206	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/3841206	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2029803/	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

Value	Dose	Analyte	Population
2782 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/3841206	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/3841206	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2029803/	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

T_1/2

Value	Dose	Co-administered	Analyte	Population
11.4 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2029803/	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

Dose	Population	Adverse 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: https://pubmed.ncbi.nlm.nih.gov/2591467	healthy, 35 years n = 8 Health Status: healthy Age Group: 35 years Sex: M+F Population Size: 8 Sources: https://pubmed.ncbi.nlm.nih.gov/2591467	Sources: https://pubmed.ncbi.nlm.nih.gov/2591467
500 mg 1 times / day steady, oral Dose: 500 mg, 1 times / day Route: oral Route: steady Dose: 500 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/26017328	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: https://pubmed.ncbi.nlm.nih.gov/26017328	Disc. AE: Impaired renal function, Thrombocytopenia... AEs leading to discontinuation/dose reduction: Impaired renal function (2 patients) Thrombocytopenia (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/26017328

AEs

AE	Significance	Dose	Population
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: https://pubmed.ncbi.nlm.nih.gov/26017328	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: https://pubmed.ncbi.nlm.nih.gov/26017328
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: https://pubmed.ncbi.nlm.nih.gov/26017328	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: https://pubmed.ncbi.nlm.nih.gov/26017328

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OAT1 554 UGT enzymes 4 UGT1A1 192 UGT1A9 113 UGT2B7 141	UGT enzymes 18 UGT1A8 266 UGT1A10 273 UGT2B7 362

Drug as perpetrator

Target	Modality	Activity
UGT enzymes 4	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/17763456/	no
UGT1A9 118	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/25522350/	yes [IC50 19.4 uM]
UGT1A1 240	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/25522350/	yes [IC50 33 uM]
UGT2B7 152	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/17200831/	yes [IC50 51 uM]
OAT1 558	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/10991954/	yes

Drug as victim

Target	Modality	Activity
UGT1A10 273	substrate 3113 Sources: https://pubmed.ncbi.nlm.nih.gov/10497143/	no
UGT enzymes 18	substrate 3113 Sources: https://pubmed.ncbi.nlm.nih.gov/8867997/	yes
UGT1A8 266	substrate 3113 Sources: https://pubmed.ncbi.nlm.nih.gov/10497143/	yes
UGT2B7 362	substrate 3113 Sources: https://pubmed.ncbi.nlm.nih.gov/8423545/	yes

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:39669	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:39669
ChemicalBook	CB9674965	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB9674965
MolPort	MolPort-001-727-460	https://www.molport.com/shop/molecule-link/MolPort-001-727-460
ZINC	ZINC000000020243	http://zinc15.docking.org/substances/ZINC000000020243
eMolecules	537237	https://www.emolecules.com/cgi-bin/more?vid=537237

PubMed

Title	Date	PubMed
		18465255
Preparation of solid dispersions of nonsteroidal anti-inflammatory drugs with acrylic polymers and studies on mechanisms of drug-polymer interactions.	2002	12916947
An improved resazurin-based cytotoxicity assay for hepatic cells.	2002	12083422
Solid dispersions of diflunisal-PVP: polymorphic and amorphous states of the drug.	2002 Jul	12149965
Physicochemical properties of amorphous salt of cimetidine and diflunisal system.	2002 Jul 25	12100849
Self-association and cyclodextrin solubilization of drugs.	2002 Nov	12379916
Thermodynamics of solutions. II. Flurbiprofen and diflunisal as models for studying solvation of drug substances.	2003 Aug	12907293
Method development and validation for the analysis of meloxicam in tablets by CZE.	2003 Feb 26	12609679
Synthesis and biological activities of diflunisal hydrazide-hydrazones.	2003 Nov-Dec	14642333
Effect of vehicle pretreatment on the flux, retention, and diffusion of topically applied penetrants in vitro.	2003 Sep	14567647
Utilization of animal studies to determine the effects and human risks of environmental toxicants (drugs, chemicals, and physical agents).	2004 Apr	15060191
Diflunisal analogues stabilize the native state of transthyretin. Potent inhibition of amyloidogenesis.	2004 Jan 15	14711308
Drug delivery devices based on mesoporous silicate.	2004 Jan-Feb	15168790
Selective binding to transthyretin and tetramer stabilization in serum from patients with familial amyloidotic polyneuropathy by an iodinated diflunisal derivative.	2004 Jul 15	15080795
Gastrointestinally distributed UDP-glucuronosyltransferase 1A10, which metabolizes estrogens and nonsteroidal anti-inflammatory drugs, depends upon phosphorylation.	2004 Jul 2	15117964
Inverse gene expression patterns for macrophage activating hepatotoxicants and peroxisome proliferators in rat liver.	2004 Jun 1	15135310
Thermodynamics of solutions III: comparison of the solvation of (+)-naproxen with other NSAIDs.	2004 Mar	15019002
Compounds exhibiting selective efficacy for different beta subunits of human recombinant gamma-aminobutyric acid A receptors.	2004 Nov	15210837
Photosensitizing effect of some nonsteroidal antiinflammatory drugs on natural and artificial membranes: dependence on phospholipid composition.	2005 Feb	15720124
Radical cross-linked albumin microspheres as potential drug delivery systems: preparation and in vitro studies.	2005 Jul-Aug	16036717
Prediction of genotoxicity of chemical compounds by statistical learning methods.	2005 Jun	15962942
Human transthyretin in complex with iododiflunisal: structural features associated with a potent amyloid inhibitor.	2005 Jun 1	15689188
Dendrimers as potential drug carriers. Part I. Solubilization of non-steroidal anti-inflammatory drugs in the presence of polyamidoamine dendrimers.	2005 Nov	16153746
Role of monocarboxylic acid transporters in the cellular uptake of NSAIDs.	2005 Sep	16105239
pH-sensitive hydrogels based on bovine serum albumin for oral drug delivery.	2006 Apr 7	16490328
Orally administered diflunisal stabilizes transthyretin against dissociation required for amyloidogenesis.	2006 Dec	17107884
Diflunisal stabilizes familial amyloid polyneuropathy-associated transthyretin variant tetramers in serum against dissociation required for amyloidogenesis.	2006 Dec	17028027
Prediction of plasma protein binding displacement and its implications for quantitative assessment of metabolic drug-drug interactions from in vitro data.	2006 Dec	16937340
Allosteric modulation of [3H]EBOB binding to GABAA receptors by diflunisal analogues.	2006 Dec	16884828
Pharmaceutical quality control of acid and neutral drugs based on competitive self-assembly in amphiphilic systems.	2006 Jan	16365667
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	16278927
Drug Insight: emerging therapies for amyloidosis.	2006 May	16932439
Cell based screening of inhibitors of transthyretin aggregation.	2006 Sep 29	16904635
Comparison of inhibition potentials of drugs against zidovudine glucuronidation in rat hepatocytes and liver microsomes.	2007 Apr	17267620
Pre-emptive analgesia for removal of nasal packing: A double-blind placebo controlled study.	2007 Dec	17337141
Inhibitory potential of nonsteroidal anti-inflammatory drugs on UDP-glucuronosyltransferase 2B7 in human liver microsomes.	2007 Feb	17200831
A comparison of pre-emptive analgesic efficacy of diflunisal and lornoxicam for postoperative pain management: a prospective, randomized, single-blind, crossover study.	2007 Feb	17157478
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	17386526
Synthesis of some novel heterocyclic compounds derived from diflunisal hydrazide as potential anti-infective and anti-inflammatory agents.	2007 Jul	17418454
FluSTAR, a novel influenza surveillance system: outcomes from the 2005-2006 flu season.	2007 Sep	17902286
100,000-fold concentration of anions in capillary zone electrophoresis using electroosmotic flow controlled counterflow isotachophoretic stacking under field amplified conditions.	2008 Aug 15	18627177
Molecular interactions in lipophilic environments studied by electrochemistry at interfaces between immiscible electrolyte solutions.	2008 Jan 1	18052132
Species differences in inhibition potential of nonsteroidal anti-inflammatory drugs against estradiol 3beta-glucuronidation between rats, dogs, and humans.	2008 Jul	17763456
The modulation of transthyretin tetramer stability by cysteine 10 adducts and the drug diflunisal. Direct analysis by fluorescence-detected analytical ultracentrifugation.	2008 May 2	18326041
Chemical substructures that enrich for biological activity.	2008 Nov 1	18784118
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	18950779
In vitro inhibition of salicylic acid derivatives on human cytosolic carbonic anhydrase isozymes I and II.	2008 Oct 15	18819808
Simultaneous determination of naproxen and diflunisal using synchronous luminescence spectrometry.	2008 Sep	18256908
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	18619534
Simultaneous determination of two anti-inflammatory drugs in serum using isopotential fluorimetry.	2008 Sep 5	18721539

Patents

Sample Use Guides

In Vivo Use Guide

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

In Vitro Use Guide

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

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Name

Type

Language

DIFLUNISAL

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