Identification

Name
Acemetacin
Accession Number
DB13783
Type
Small Molecule
Groups
Approved, Experimental, Investigational
Description

Acemetacin is a carboxymethyl ester of indometacin. It is a potent non-steroidal anti-inflammatory drug, derived from the indol-3-acetic acid, whose activity is thought to be mainly through its active metabolite indomethacin.[1] In clinical trials, acemetacin exhibits a better gastric tolerability compared to its active metabolite indometacin.[6] It was developed by E. Merck and Company in Germany as an attempt to provide a safer drug but other than the amelioration on the gastrointestinal effects, the metabolism of acetamicin led to the formation of indomethacin and it kept the same side effects.[7]

Structure
Thumb
Synonyms
  • Acemetacin
  • acemetacina
  • acemetacine
  • acemetacinum
  • indometacin carboxymethyl ester
  • indometacin glycolic ester
  • indomethacin carboxymethyl ester
  • indomethacin glycolic ester
External IDs
K 708 / K-708 / TV-1322 / TVX 3322
International/Other Brands
Acemetacin Heumann (Heumann) / Acemetacin Stada (Stada) / Acemetacin von ct (ct-Arzneimittel) / Acemix (Bioprogress) / Altren (Rorer) / Analgen (Celtia) / Emflex (Merck Serono) / Esplendol (Fher) / Flamarion (Syncro) / Gynalgia (Syncro) / Mostanol (Boehringer Ingelheim) / Oldan (Europharma) / Rantudil (Bayer or Bial) / Rheutrop (Kolassa or Tropon) / Solart (Bioindustria) / Tilur (Drossapharm)
Categories
UNII
5V141XK28X
CAS number
53164-05-9
Weight
Average: 415.83
Monoisotopic: 415.082265
Chemical Formula
C21H18ClNO6
InChI Key
FSQKKOOTNAMONP-UHFFFAOYSA-N
InChI
InChI=1S/C21H18ClNO6/c1-12-16(10-20(26)29-11-19(24)25)17-9-15(28-2)7-8-18(17)23(12)21(27)13-3-5-14(22)6-4-13/h3-9H,10-11H2,1-2H3,(H,24,25)
IUPAC Name
2-({2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetyl}oxy)acetic acid
SMILES
COC1=CC2=C(C=C1)N(C(=O)C1=CC=C(Cl)C=C1)C(C)=C2CC(=O)OCC(O)=O

Pharmacology

Indication

Acemetacin is not FDA, Canada or EMA approved, but in the countries where it is marketed it is indicated for the symptomatic treatment of pain and swelling in acute inflammation of the joints in rheumathoid arthritis, osteoarthritis, low back pain and post-surgical pain.[11] It is also indicated for the treatment of chronic inflammation of the joints in presence of rheumatoid arthritis, treatment of ankylosing spondylitis, treatment of irritation in the joints and spinal column caused by degenerative disorders, treatment of inflammatory soft-tissue rheumatism syndrome and painful swelling and inflammation caused by injury.[10, 12]

Pharmacodynamics

The effect of acemetacin causes a weak reduction of prostaglandin synthesis which generates an anti-inflammatory and analgesic effect. The weak inhibition of prostaglandin reduces significantly the damage caused in the mucous membrane of the gastrointestinal tract. Studies have shown that acemetacin strongly inhibits the release of histamine from mast cells and the generation of hyperthermia. Acemetacin effect also causes changes in systolic and diastolic blood pressure as well as inhibition of platelet aggregation.[2]

Mechanism of action

Acemetacin is a non-selective inhibitor of the production of pro-inflammatory mediators derived from the action of the enzyme COX. COX is essential for the synthesis of prostaglandin E2 and F2 which are molecules derived from fatty acids and stored in the cell membrane.[8] Acetometacine is metabolized and forms its major metabolite indometacin which is also a non-selective inhibitor of COX and exhibits the capacity to inhibit the motility of polymorphonuclear leukocytes and decreased cerebral flow by modulating the nitric oxide pathway and vasoconstriction.[7]

TargetActionsOrganism
AProstaglandin G/H synthase 1
antagonist
Human
AProstaglandin G/H synthase 2
antagonist
Human
Absorption

After 8 days of oral administration twice daily of acemetacin there was an age-dependant Cmax of 276.8 ng/ml in elderly compared to 187 ng/ml for younger individuals. There was also a Tmax of 2.5 h and AUC in a range of 483-712 ng h/ml.[3] The bioavailability of acemetacin after repeated doses is aproximately 66% in plasma and 64% in urine.[4]

Volume of distribution

The apparent volume of distribution of acemetacin is in a range of 0.5-0.7 L/kg.[9]

Protein binding

Acemetacin is found highly bound to plasma proteins, reaching a percentage higher than 90% of the administered dose.[9]

Metabolism

Acemetacin is highly metabolized and degraded by esterolytic cleavage to form its major and active metabolite indometacin. It presents other inactive metabolites made by reaction of O-demethylation, N-desacylation and part of them are also transformed by conjugation with glucuronic acid.[9]

Route of elimination

The elimination of acemetacin is divided in renal elimination that covers 40% of the complete administered dose and the restant 60% is excreted in feces.[9]

Half life

The elimination half-life of acemetacin after steady-state is 4.5 hours.[4]

Clearance

Intravenous administration of acemetacin in healthy subjects reported a clearance rate of 4.59 ml min/kg.[5]

Toxicity

The pharmacological activity of acemetacin causes blockage of prostaglandin synthesis. Prostaglandin is one of the mediators of renal blood flow and glomerular filtration thus, acemetacin causes a decreased renal function, transient renal insufficiency, interstitial nephritis and papillary necrosis especially in elderly patients, patients with congestive heart failure, hepatic cirrhosis and impaired renal function.[9]

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of bleeding and hemorrhage can be increased when (R)-warfarin is combined with Acemetacin.
(S)-WarfarinThe risk or severity of bleeding and hemorrhage can be increased when (S)-Warfarin is combined with Acemetacin.
1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic AcidThe risk or severity of renal failure, hyperkalemia, and hypertension can be increased when Acemetacin is combined with 1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid.
1-benzylimidazoleThe risk or severity of hypertension can be increased when 1-benzylimidazole is combined with Acemetacin.
2,5-Dimethoxy-4-ethylamphetamineThe risk or severity of hypertension can be increased when 2,5-Dimethoxy-4-ethylamphetamine is combined with Acemetacin.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of hypertension can be increased when Acemetacin is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3,4-MethylenedioxyamphetamineThe risk or severity of hypertension can be increased when 3,4-Methylenedioxyamphetamine is combined with Acemetacin.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of hypertension can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Acemetacin.
4-hydroxycoumarinThe risk or severity of bleeding and hemorrhage can be increased when 4-hydroxycoumarin is combined with Acemetacin.
4-MethoxyamphetamineThe risk or severity of hypertension can be increased when 4-Methoxyamphetamine is combined with Acemetacin.
Food Interactions
Not Available

References

General References
  1. Wada Y, Nakamura M, Kogo H, Aizawa Y: Inhibitory effect of acemetacin, a prodrug of indomethacin, on prostaglandin E2 release from inflamed synovial tissue. Jpn J Pharmacol. 1984 Apr;34(4):468-70. [PubMed:6587139]
  2. Jacobi H, Dell HD: [On the pharmacodynamics of acemetacin (author's transl)]. Arzneimittelforschung. 1980;30(8A):1348-62. [PubMed:6968219]
  3. Jones RW, Collins AJ, Notarianni LJ, Sedman E: The comparative pharmacokinetics of acemetacin in young subjects and elderly patients. Br J Clin Pharmacol. 1991 May;31(5):543-5. [PubMed:1888622]
  4. Dell HD, Doersing M, Fischer W, Jacobi H, Kamp R, Kohler G, Schollnhammer G: [Metabolism and pharmacokinetics of acemetacin in man (author's transl)]. Arzneimittelforschung. 1980;30(8A):1391-8. [PubMed:7191306]
  5. Ochs HR, Schuppan U, Greenblatt DJ, Abernethy DR: Reduced distribution and clearance of acetaminophen in patients with congestive heart failure. J Cardiovasc Pharmacol. 1983 Jul-Aug;5(4):697-9. [PubMed:6193370]
  6. Acton A. (2011). Issues in Pharmacology, Pharmacy, Drug Research and Drug Innovation . ScholarlyEditions.
  7. Sneader W. (2005). Drug discovery a history. Wiley.
  8. Chian R., Nargund G. and Huang J. (2017). Development of In vitro maturation for human oocytes. Springer.
  9. Seyffart G. (1992). Drug dosage in renal insufficiency (2nd ed.). Springer Science+Business Media Dordrecht.
  10. Rantudil label [Link]
  11. Emflex label [Link]
  12. Vademecum [Link]
External Links
KEGG Drug
D01582
PubChem Compound
1981
PubChem Substance
347829316
ChemSpider
1904
BindingDB
50336272
ChEBI
31162
ChEMBL
CHEMBL189171
PharmGKB
PA166049184
Wikipedia
Acemetacin
ATC Codes
M01AB11 — Acemetacin
MSDS
Download (32.4 KB)

Clinical Trials

Clinical Trials
Not Available

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)151.5ºC'MSDS'
boiling point (°C)637ºC'MSDS'
water solubilitySlightly soluble'MSDS'
logP4.49Lead Optimization for Medicinal Chemists. Zaragoza Dorwald F. (2012). Wiley-VCH
pKa2.6'MSDS'
Predicted Properties
PropertyValueSource
Water Solubility0.00229 mg/mLALOGPS
logP3.71ALOGPS
logP3.15ChemAxon
logS-5.3ALOGPS
pKa (Strongest Acidic)3.26ChemAxon
pKa (Strongest Basic)-2.3ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area94.83 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity105.66 m3·mol-1ChemAxon
Polarizability41.23 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
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/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-004i-9000000000-a88b981f972b7490041c
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-004i-9000000000-5022ac71b0218e05c255
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-004i-9010000000-7313a9e1ea4e6eadd36a
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-004i-9010000000-06c9e0b7be55ee33883e
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-004i-9010000000-c018c587e277a577b1dc
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-004i-9110000000-579c64350d45101c2939
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-014i-0210900000-e952722b47bc6f5bce93
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-000i-0900000000-c5202d3fb48f6df18dce
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-000i-0900000000-b5f7e4a388e86e743206
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-000i-0900000000-47ab4028894c896b53b3
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-000i-0900000000-50c13e48179e8e0a0fb2
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-000i-0911000000-28e04265af736ccc17a9
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-000i-0900000000-85d2686103fd853155ba
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-000i-0900000000-5add7b0f737e82efdd15
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-000i-0900000000-095e5b098c5f7dd6bc5a
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-000i-0900000000-8939159ece125ac8a14b
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-002r-1900000000-f0f214f31c71a92a8b3d
MS/MS Spectrum - , positiveLC-MS/MSsplash10-000i-0901200000-1a6af5ef67d07b4da751
MS/MS Spectrum - , positiveLC-MS/MSsplash10-000i-3900000000-cf46a091c4414a82a401

Taxonomy

Description
This compound belongs to the class of organic compounds known as benzoylindoles. These are organic compounds containing an indole attached to a benzoyl moiety through the acyl group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Indoles and derivatives
Sub Class
Benzoylindoles
Direct Parent
Benzoylindoles
Alternative Parents
Indole-3-acetic acid derivatives / Indolecarboxylic acids and derivatives / 3-alkylindoles / 4-halobenzoic acids and derivatives / Anisoles / Benzoyl derivatives / Alkyl aryl ethers / Chlorobenzenes / Dicarboxylic acids and derivatives / Aryl chlorides
show 11 more
Substituents
Benzoylindole / Indole-3-acetic acid derivative / Indolecarboxylic acid derivative / 4-halobenzoic acid or derivatives / Halobenzoic acid or derivatives / 3-alkylindole / Benzoic acid or derivatives / Indole / Anisole / Benzoyl
show 27 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
monocarboxylic acid, carboxylic ester, monochlorobenzenes, N-acylindole, indol-3-yl carboxylic acid (CHEBI:31162)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
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. Sneader W. (2005). Drug discovery a history. Wiley.
  2. Chian R., Nargund G. and Huang J. (2017). Development of In vitro maturation for human oocytes. Springer.
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
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. Sneader W. (2005). Drug discovery a history. Wiley.
  2. Chian R., Nargund G. and Huang J. (2017). Development of In vitro maturation for human oocytes. Springer.

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Glucuronosyltransferase activity
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds.Its unique specificity for 3,4-catechol estrogens and estriol su...
Gene Name
UGT2B7
Uniprot ID
P16662
Uniprot Name
UDP-glucuronosyltransferase 2B7
Molecular Weight
60694.12 Da
References
  1. Seyffart G. (1992). Drug dosage in renal insufficiency (2nd ed.). Springer Science+Business Media Dordrecht.

Transporters

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Transporter activity
Specific Function
Mediates export of organic anions and drugs from the cytoplasm. Mediates ATP-dependent transport of glutathione and glutathione conjugates, leukotriene C4, estradiol-17-beta-o-glucuronide, methotre...
Gene Name
ABCC1
Uniprot ID
P33527
Uniprot Name
Multidrug resistance-associated protein 1
Molecular Weight
171589.5 Da
References
  1. Dittmar T. and Zanker K. (2009). Stem cell biology in health and disease. Springer.

Drug created on June 23, 2017 14:48 / Updated on December 14, 2018 13:19