Identification

Name
Aceclofenac
Accession Number
DB06736
Type
Small Molecule
Groups
Approved, Investigational
Description

Aceclofenac is a non-steroidal anti-inflammatory drug (NSAID) with marked anti-inflammatory and analgesic properties. 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. It is orally administered for the relief of pain and inflammation in osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. 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.

Structure
Thumb
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
International/Other Brands
Cincofen / Clanza / Hifenac
Categories
UNII
RPK779R03H
CAS number
89796-99-6
Weight
Average: 354.18
Monoisotopic: 353.0221633
Chemical Formula
C16H13Cl2NO4
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

Pharmacology

Indication

Indicated for the relief of pain and inflammation in osteoarthritis, rheumatoid arthritis and ankylosing spondylitis.

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 [A19763]. 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
Human
AProstaglandin G/H synthase 1
inhibitor
Human
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].

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].

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].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of gastrointestinal bleeding can be increased when Aceclofenac is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of gastrointestinal bleeding can be increased when Aceclofenac is combined with (S)-Warfarin.
1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic AcidThe risk or severity of renal failure, hyperkalemia, and hypertension can be increased when Aceclofenac is combined with 1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid.
4-hydroxycoumarinThe risk or severity of gastrointestinal bleeding can be increased when Aceclofenac is combined with 4-hydroxycoumarin.
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.
AbirateroneThe metabolism of Aceclofenac can be decreased when combined with Abiraterone.
AcarboseAceclofenac may decrease the excretion rate of Acarbose which could result in a higher serum level.
AcebutololAceclofenac may decrease the antihypertensive activities of Acebutolol.
AcemetacinThe risk or severity of adverse effects can be increased when Aceclofenac is combined with Acemetacin.
Food Interactions
Not Available

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. [PubMed:25045671]
  2. Legrand E: Aceclofenac in the management of inflammatory pain. Expert Opin Pharmacother. 2004 Jun;5(6):1347-57. [PubMed:15163279]
  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. [PubMed:23581533]
  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. [PubMed:19588436]
  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. [PubMed:21277837]
  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. [PubMed:8799688]
  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. [PubMed:11511027]
  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. [PubMed:8730134]
  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.
  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. [PubMed:26839834]
  11. UK Medicines and Healthcare products Regulatory Agency: ACECLOFENAC 100MG TABLETS product information [Link]
  12. DailyMed: CLANZA CR- aceclofenac tablet, film coated [Link]
External Links
KEGG Drug
D01545
PubChem Compound
71771
PubChem Substance
347827785
ChemSpider
64809
BindingDB
50109016
ChEBI
31159
ChEMBL
CHEMBL93645
PharmGKB
PA166049185
Wikipedia
Aceclofenac
ATC Codes
M01AB16 — AceclofenacM02AA25 — Aceclofenac
MSDS
Download (45.6 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Enrolling by InvitationTreatmentHealthy Volunteers1
2, 3CompletedPreventionIrreversible Pulpitis1
2, 3CompletedPreventionSymptomatic Irreversible Pulpitis1
3CompletedTreatmentDisorder of Urinary Stent1
4CompletedPreventionNSAID-associated Gastroduodenal Injury1
4CompletedTreatmentOsteoarthritis (OA)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
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
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
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

Taxonomy

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
Aniline or substituted anilines / 1,3-dichlorobenzene / Aryl chloride / Aryl halide / Dicarboxylic acid or derivatives / Amino acid or derivatives / Amino acid / Carboxylic acid ester / Carboxylic acid derivative / Secondary amine
show 13 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
monocarboxylic acid, carboxylic ester, secondary amino compound, dichlorobenzene, amino acid (CHEBI:31159)

Targets

Kind
Protein
Organism
Human
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. [PubMed:15163279]
Kind
Protein
Organism
Human
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. [PubMed:15163279]

Enzymes

Kind
Protein
Organism
Human
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. [PubMed:19515014]
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  3. Rendic S: Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448. [PubMed:11996015]

Drug created on August 31, 2010 14:49 / Updated on November 02, 2018 06:19