Aceclofenac

Identification

Generic Name
Aceclofenac
DrugBank Accession Number
DB06736
Background

Aceclofenac is an oral non-steroidal anti-inflammatory drug (NSAID) with marked anti-inflammatory and analgesic properties used to treat osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. It is reported to have a higher anti-inflammatory action or at least comparable effects than conventional NSAIDs in double-blind studies 2,3,5. Aceclofenac potently inhibits the cyclo-oxygenase enzyme (COX) that is involved in the synthesis of prostaglandins, which are inflammatory mediators that cause pain, swelling, inflammation, and fever. Aceclofenac belongs to BCS Class II as it possesses poor aqueous solubility 2. It displays high permeability to penetrate into synovial joints where in patients with osteoarthritis and related conditions, the loss of articular cartilage in the area causes joint pain, tenderness, stiffness, crepitus, and local inflammation 1. Aceclofenac is also reported to be effective in other painful conditions such as dental and gynaecological conditions 7. In 1991, aceclofenac was developed as an analog of a commonly prescribed NSAID, Diclofenac, via chemical modification in effort to improve the gastrointestinal tolerability of the drug. It is a more commonly prescribed drug in Europe.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 354.18
Monoisotopic: 353.0221633
Chemical Formula
C16H13Cl2NO4
Synonyms
  • 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid carboxymethyl ester
  • 2-[(2,6-dichlorophenyl)amino]phenylacetoxyacetic acid
  • 2-[(2',6'-dichlorophenyl)amino]phenylacetoxyacetic acid
  • Aceclofenac
  • Acéclofénac
  • Aceclofenac betadex
  • Aceclofenaco
  • Aceclofenacum
  • glycolic acid [o-(2,6-dichloroanilino)phenyl]acetate ester

Pharmacology

Indication

Aceclofenac is indicated for the relief of pain and inflammation in osteoarthritis, rheumatoid arthritis and ankylosing spondylitis.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Symptomatic treatment ofAnkylosing spondylitis (as)••••••••••••
Symptomatic treatment ofOsteoarthritis (oa)••••••••••••
Symptomatic treatment ofRheumatoid arthritis••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Aceclofenac is a NSAID that inhibits both isoforms of COX enzyme, a key enzyme involved in the inflammatory cascade. COX-1 enzyme is a constitutive enzyme involved in prostacyclin production and protective functions of gastric mucosa whereas COX-2 is an inducible enzyme involved in the production of inflammatory mediators in response to inflammatory stimuli. Aceclofenac displays more selectivity towards COX-2 (IC50 of 0.77uM) than COX-1 (IC50 of >100uM), which promotes its gastric tolerance compared to other NSAIDs. The primary metabolite, 4'-hydroxyaceclofenac, also minimally inhibits COX-2 with IC50 value of 36uM 2. Although the mode of action of aceclofenac is thought to mainly arise from the inhibition of synthesis of prostaglandins (PGE2), aceclofenac also inhibits the production of inflammatory cytokines, interleukins (IL-1β, IL-6), and tumor necrosis factors (TNF) 1,2. It is also reported that aceclofenac also affects the cell adhesion molecules from neutrophils 8. Aceclofenac also targets the synthesis of glycosaminoglycan and mediates chrondroprotective effects 1.

Mechanism of action

Through COX-2 inhibition, aceclofenac downregulates the production of various inflammatory mediators including prostaglandin E2 (PGE2), IL-1β, and TNF from the arachidonic acid (AA) pathway. Inhibition of IL-6 is thought to be mediated by diclofenac converted from aceclofenac 6. Suppressed action of inflammatory cytokines decreases the production of reactive oxygen species. Aceclofenac is shown to decreased production of nitrous oxide in human articular chondrocytes 2. In addition, aceclofenac interferes with neutrophil adhesion to endothelium by decreasing the expression of L-selectin (CD62L), which is a cell adhesion molecule expressed on lymphocytes 8. Aceclofenac is proposed to stimulate the synthesis of glycosaminoglycan in human osteoarthritic cartilage which may be mediated through its inhibitory action on IL-1 production and activity 1. The chrondroprotective effects are generated by 4'-hydroxyaceclofenac which suppresses IL-1 mediated production of promatrix metalloproteinase-1 and metalloproteinase-3 and interferes with the release of proteoglycan from chrondrocytes 1,2,7.

TargetActionsOrganism
AProstaglandin G/H synthase 2
inhibitor
Humans
AProstaglandin G/H synthase 1
inhibitor
Humans
Absorption

Aceclofenac is rapidly and completely absorbed from the gastrointestinal tract and circulates mainly as unchanged drug following oral administration. Peak plasma concentrations are reached around 1.25 to 3 hours post-ingestion, and the drug penetrates into the synovial fluid where the concentration may reach up to 60% of that in the plasma 11. There is no accumulation in regular dosing, with similar maximum plasma concentration (Cmax) and time to reach peak plasma concentration (Tmax) after single and multiple doses 2.

Volume of distribution

The volume of distribution is approximately 25 L 11.

Protein binding

It is reported to be highly protein-bound (>99%) 11.

Metabolism

4'-hydroxyaceclofenac is the main metabolite detected in plasma however other minor metabolites include diclofenac, 5-hydroxyaceclofenac, 5-hydroxydiclofenac, and 4'-hydroxydiclofenac 2. It is probable that the metabolism of aceclofenac is mediated by CYP2C9 9.

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Route of elimination

The main route of elimination is via the urine where the elimination accounts for 70-80% of clearance of the drug 2. Approximately two thirds of the administered dose is excreted via the urine, mainly as glucuronidated and hydroxylated forms of aceclofenac 11. About 20% of the dose is excreted into feces 6.

Half-life

The mean plasma elimination half-life is approximately 4 hours 11.

Clearance

The mean clearance rate is approximately 5 L/h 9.

Adverse Effects
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Toxicity

Some common adverse effects include gastro-intestinal disorders (dyspepsia, abdominal pain, nausea), rash, ruber, urticaria, symptoms of enuresis, headache, dizziness, and drowsiness 12. Oral LD50 value in rats is 130 mg/kg MSDS.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirAceclofenac may decrease the excretion rate of Abacavir which could result in a higher serum level.
AbciximabThe risk or severity of bleeding and hemorrhage can be increased when Aceclofenac is combined with Abciximab.
AcebutololAceclofenac may decrease the antihypertensive activities of Acebutolol.
AcemetacinThe risk or severity of adverse effects can be increased when Aceclofenac is combined with Acemetacin.
AcenocoumarolThe risk or severity of bleeding and hemorrhage can be increased when Aceclofenac is combined with Acenocoumarol.
Food Interactions
  • Take with or without food.

Products

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International/Other Brands
Cincofen / Clanza / Hifenac
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Clanza CRTablet, film coated200 mg/1OralUnited Douglas Pharm., Inc.2011-05-12Not applicableUS flag

Categories

ATC Codes
M01AB16 — AceclofenacM02AA25 — Aceclofenac
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as dichlorobenzenes. These are compounds containing a benzene with exactly two chlorine atoms attached to it.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Halobenzenes
Direct Parent
Dichlorobenzenes
Alternative Parents
Aniline and substituted anilines / Dicarboxylic acids and derivatives / Aryl chlorides / Carboxylic acid esters / Amino acids / Secondary amines / Carboxylic acids / Organopnictogen compounds / Organochlorides / Organic oxides
show 2 more
Substituents
1,3-dichlorobenzene / Amine / Amino acid / Amino acid or derivatives / Aniline or substituted anilines / Aromatic homomonocyclic compound / Aryl chloride / Aryl halide / Carbonyl group / Carboxylic acid
show 13 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
monocarboxylic acid, carboxylic ester, secondary amino compound, dichlorobenzene, amino acid (CHEBI:31159)
Affected organisms
Not Available

Chemical Identifiers

UNII
RPK779R03H
CAS number
89796-99-6
InChI Key
MNIPYSSQXLZQLJ-UHFFFAOYSA-N
InChI
InChI=1S/C16H13Cl2NO4/c17-11-5-3-6-12(18)16(11)19-13-7-2-1-4-10(13)8-15(22)23-9-14(20)21/h1-7,19H,8-9H2,(H,20,21)
IUPAC Name
2-[(2-{2-[(2,6-dichlorophenyl)amino]phenyl}acetyl)oxy]acetic acid
SMILES
OC(=O)COC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl

References

General References
  1. Raza K, Kumar M, Kumar P, Malik R, Sharma G, Kaur M, Katare OP: Topical delivery of aceclofenac: challenges and promises of novel drug delivery systems. Biomed Res Int. 2014;2014:406731. doi: 10.1155/2014/406731. Epub 2014 Jun 18. [Article]
  2. Legrand E: Aceclofenac in the management of inflammatory pain. Expert Opin Pharmacother. 2004 Jun;5(6):1347-57. [Article]
  3. Pareek A, Chandurkar N: Comparison of gastrointestinal safety and tolerability of aceclofenac with diclofenac: a multicenter, randomized, double-blind study in patients with knee osteoarthritis. Curr Med Res Opin. 2013 Jul;29(7):849-59. doi: 10.1185/03007995.2013.795139. Epub 2013 Apr 30. [Article]
  4. Moore RA, Derry S, McQuay HJ: Single dose oral aceclofenac for postoperative pain in adults. Cochrane Database Syst Rev. 2009 Jul 8;(3):CD007588. doi: 10.1002/14651858.CD007588.pub2. [Article]
  5. Pareek A, Chandurkar N, Gupta A, Sirsikar A, Dalal B, Jesalpura B, Mehrotra A, Mukherjee A: Efficacy and safety of aceclofenac-cr and aceclofenac in the treatment of knee osteoarthritis: a 6-week, comparative, randomized, multicentric, double-blind study. J Pain. 2011 May;12(5):546-53. doi: 10.1016/j.jpain.2010.10.013. Epub 2011 Feb 1. [Article]
  6. Brogden RN, Wiseman LR: Aceclofenac. A review of its pharmacodynamic properties and therapeutic potential in the treatment of rheumatic disorders and in pain management. Drugs. 1996 Jul;52(1):113-24. doi: 10.2165/00003495-199652010-00008. [Article]
  7. Dooley M, Spencer CM, Dunn CJ: Aceclofenac: a reappraisal of its use in the management of pain and rheumatic disease. Drugs. 2001;61(9):1351-78. [Article]
  8. Gonzalez-Alvaro I, Carmona L, Diaz-Gonzalez F, Gonzalez-Amaro R, Mollinedo F, Sanchez-Madrid F, Laffon A, Garcia-Vicuna R: Aceclofenac, a new nonsteroidal antiinflammatory drug, decreases the expression and function of some adhesion molecules on human neutrophils. J Rheumatol. 1996 Apr;23(4):723-9. [Article]
  9. Ghosh S, Barik BB: A Comparative Study of the Pharmacokinetics of Conventional and Sustained-release Tablet Formulations of Aceclofenac in Healthy Male Subjects Tropical Journal of Pharmaceutical Research. 2010 September 1;9(4):395-399. [Article]
  10. Dahiya S, Kaushik A, Pathak K: Improved Pharmacokinetics of Aceclofenac Immediate Release Tablets Incorporating its Inclusion Complex with Hydroxypropyl-beta-Cyclodextrin. Sci Pharm. 2015 Feb 2;83(3):501-10. doi: 10.3797/scipharm.1509-07. Print 2015 Jul-Sep. [Article]
  11. UK Medicines and Healthcare products Regulatory Agency: ACECLOFENAC 100MG TABLETS product information [Link]
  12. DailyMed Label: Clanza CR (Aceclofenac) Oral Tablets [Link]
KEGG Drug
D01545
PubChem Compound
71771
PubChem Substance
347827785
ChemSpider
64809
BindingDB
50109016
RxNav
16689
ChEBI
31159
ChEMBL
CHEMBL93645
ZINC
ZINC000003805798
PharmGKB
PA166049185
Wikipedia
Aceclofenac
MSDS
Download (45.6 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedBasic ScienceRheumatoid Arthritis1
4CompletedPreventionNSAID-associated Gastroduodenal Injury1
4CompletedTreatmentOsteoarthritis (OA)1
4CompletedTreatmentOsteoarthritis of the Knee1
3CompletedTreatmentDisorder of Urinary Stent1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral100 mg
Tablet, film coatedOral100 mg
Injection, powder, lyophilized, for solutionParenteral0.15 g
Tablet, film coatedOral0.1 g
Tablet, film coatedOral100 mg/1
CreamTopical1.5 g
Drug delivery systemOral100.000 mg
TabletOral100.00 mg
Tablet, film coatedOral200 mg/1
CreamCutaneous1.5 g
CreamTopical1.5 %
CreamTopical1.5 G/100G
Injection, powder, for solutionIntramuscular150 MG/4ML
Powder, for suspensionOral100 MG
Suppository200 MG
CreamCutaneous1.500 g
Tablet, film coatedOral
Tablet, extended releaseOral200 mg
Tablet, coatedOral100 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)149-153MSDS
water solubilityInsoluble Wikipedia
logP2.170Dahiya S, Kaushik A, and Pathak K, 2015
Predicted Properties
PropertyValueSource
Water Solubility0.00199 mg/mLALOGPS
logP4.88ALOGPS
logP3.88Chemaxon
logS-5.2ALOGPS
pKa (Strongest Acidic)3.44Chemaxon
pKa (Strongest Basic)-2.1Chemaxon
Physiological Charge-1Chemaxon
Hydrogen Acceptor Count4Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area75.63 Å2Chemaxon
Rotatable Bond Count7Chemaxon
Refractivity86.32 m3·mol-1Chemaxon
Polarizability32.76 Å3Chemaxon
Number of Rings2Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-0udi-0094000000-f8c3fec999613f33dcf4
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-0gb9-0090000000-4e970fdc8b34b418dfb4
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-014i-0090000000-4ea83e6670ee0480c3f0
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-014i-0090000000-5eed5bf9db2e212a1e81
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-03di-0090000000-3024a6130ab2a3ec552a
MS/MS Spectrum - , positiveLC-MS/MSsplash10-03xr-2390000000-7e1719951982f5715ecd
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0fb9-0079000000-bb155d3e52b818f785c3
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-004i-9000000000-a21e7386f16ba6c0846e
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0ugi-0091000000-60e2efa30f502dfbb8b3
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0059-9030000000-a3868a809961d0db3989
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0gx0-0590000000-fc4d21212f1b82517467
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-9010000000-4f6b4c5246c3904cd57b
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-165.80246
predicted
DeepCCS 1.0 (2019)
[M+H]+168.16045
predicted
DeepCCS 1.0 (2019)
[M+Na]+174.25362
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Prostaglandin-endoperoxide synthase activity
Specific Function
Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Constitutively expressed in some tissues in physiological conditions, such as the endothelium, kidney and...
Gene Name
PTGS2
Uniprot ID
P35354
Uniprot Name
Prostaglandin G/H synthase 2
Molecular Weight
68995.625 Da
References
  1. Legrand E: Aceclofenac in the management of inflammatory pain. Expert Opin Pharmacother. 2004 Jun;5(6):1347-57. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Prostaglandin-endoperoxide synthase activity
Specific Function
Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Involved in the constitutive production of prostanoids in particular in the stomach and platelets. In gas...
Gene Name
PTGS1
Uniprot ID
P23219
Uniprot Name
Prostaglandin G/H synthase 1
Molecular Weight
68685.82 Da
References
  1. Legrand E: Aceclofenac in the management of inflammatory pain. Expert Opin Pharmacother. 2004 Jun;5(6):1347-57. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [Article]
  2. Rendic S: Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448. [Article]

Drug created at August 31, 2010 20:49 / Updated at February 03, 2022 21:01