Tolfenamic acid
Identification
- Generic Name
- Tolfenamic acid
- DrugBank Accession Number
- DB09216
- Background
Tolfenamic acid, with the formula N-(2-methyl-3-chlorphenyl)-anthranilic acid, is a nonsteroidal anti-inflammatory agent.2 It was discovered by scientists at Medica Pharmaceutical Company in Finland. It is used in the UK as a treatment for migraine under the name of Clotam.10 In the US, it presents a Status class I by the FDA. By the European Medicine Agency, it was granted in 2016 with the status of orphan for the treatment of supranuclear palsy.9
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
- Weight
- Average: 261.704
Monoisotopic: 261.05565634 - Chemical Formula
- C14H12ClNO2
- Synonyms
- Acide tolfenamique
- ácido tolfenámico
- Acidum tolfenamicum
- Tolfenamic acid
Pharmacology
- Indication
In the information for tolfenamic acid, it is stated that this drug, being an NSAID, is effective in treating the pain associated with the acute attack of migraines in adults.11
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- Pharmacodynamics
Studies have shown that tolfenamic acid presents a non-dose dependent partial inhibition of irritant-induced temperature rise as well as a dose-dependent inhibition of skin edema. By studying its NSAID properties more closely, it was noted a dose-related inhibition of serum thromboxane which indicated the inhibition of COX-1. In the same line, there was noted a inhibition of prostaglandin E2 synthesis which marks a related COX-2 inhibition.3 The maximal inhibition of thromboxane was greater than 80% as well as is proven to be a potent prostaglandin E inhibitor.4
- Mechanism of action
Tolfenamic acid inhibits the biosynthesis of prostaglandins, and it also presents inhibitory actions on the prostaglandin receptors.2 As commonly thought, the mechanism of action of tolfenamic acid is based on the major mechanism of NSAIDs which consists of the inhibition of COX-1 and COX-2 pathways to inhibit prostaglandin secretion and action and thus, to exert its anti-inflammatory and pain-blocking action. Nonetheless, some report currently indicates that tolfenamic acid inhibits leukotriene B4 chemotaxis of human polymorphonuclear leukocytes leading to an inhibition of even 25% of the chemotactic response. This activity is a not ligand specific additional anti-inflammatory mechanism of tolfenamic acid.5
Target Actions Organism AProstaglandin G/H synthase 1 antagonistHumans AProstaglandin G/H synthase 2 antagonistHumans - Absorption
Tolfenamic acid pharmacokinetic is marked by a short tmax of 0.94-2.04 h.3 It also presented a linear pharmacokinetic profile with an AUC from 13-50 mcg/ml.h if administered in a dose of 2-8 mg/kg respectively.4 The oral absorption is delayed and it gives a mean lag-time to absorption of 32 min. The peak plasma concentration of 11.1 mcg/ml.6 The bioavailability of tolfenamic acid is around 75%.8
- Volume of distribution
The volume of distribution is of 1.79-3.2 L/kg.3 When tested intravenously, the reported steady-state volume of distribution was 0.33 L/kg.6
- Protein binding
Tolfenamic acid presents high protein binding properties reaching 99.7% of the administered dose.1 Studies have studied the changes in protein binding depending on the presence of certain disorders that modify the dialysis equilibrium. These studies verify that modifications in blood creatinine, urea and bilirubin can significantly alter the concentration of unbound tolfenamic acid. The main binding structure is predicted to be related to lipid membrane structures.7
- Metabolism
The first pass metabolism accounts for 20% of the administered dose of tolfenamic acid.8 Urine metabolite studies have demonstrated the identification of five metabolites from which three of them are monohydroxylated, one is monohydroxylated and hydroxylated and one last metabolite that presented and oxidized methyl group to form a carboxyl group.8 Two of these hydroxylated metabolites are N-(2-hydroxymethyl-3-chlorophenyl)-anthranilic acid and N-(2-hydroxymethyl-3-chloro-4-hydroxyphenyl)-anthranilic acid.12
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- Route of elimination
Tolfenamic acid is cleared relatively fast and it undergoes by hepatic metabolism where the produced metabolites are renally cleared as glucuronic acid conjugates.8 Most of the elimination occurs by extrarenal mechanisms in which the unchanged drug together with its glucuronide in urine accounts for only 8.8% of the administered dose.1
- Half-life
The estimated half-life of tolfenamic acid is 8.01-13.50 hours.3 When tested intravenously, the reported half-life was 6.1h.6
- Clearance
The estimated clearance rate of tolfenamic acid is 0.142-0.175 L.h/kg.3 When tested intravenously, the reported clearance rate was 72.4 ml.h/kg.6
- Adverse Effects
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- Toxicity
Tolfenamic acid has a relatively low acute toxicity with LD50 values in 200-1000 mg/kg. The metabolites of tolfenamic acid are reported to have an even less important toxicity. Some of the expected toxicity is related to the presence of gastrointestinal effects such as gut ulceration and renal papillitis.12
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
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- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbacavir Tolfenamic acid may decrease the excretion rate of Abacavir which could result in a higher serum level. Abametapir The serum concentration of Tolfenamic acid can be increased when it is combined with Abametapir. Abciximab The risk or severity of bleeding and hemorrhage can be increased when Tolfenamic acid is combined with Abciximab. Acebutolol Tolfenamic acid may decrease the antihypertensive activities of Acebutolol. Aceclofenac The risk or severity of adverse effects can be increased when Aceclofenac is combined with Tolfenamic acid. - Food Interactions
- Not Available
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- International/Other Brands
- Clotam (GEA Farmaceutisk Fabrik)
Categories
- ATC Codes
- M01AG02 — Tolfenamic acid
- Drug Categories
- Acids, Carbocyclic
- Agents causing hyperkalemia
- Agents that produce hypertension
- Aminobenzoates
- Analgesics
- Analgesics, Non-Narcotic
- Anti-Inflammatory Agents
- Anti-Inflammatory Agents, Non-Steroidal
- Antiinflammatory and Antirheumatic Products
- Antiinflammatory and Antirheumatic Products, Non-Steroids
- Antirheumatic Agents
- Benzene Derivatives
- Benzoates
- Bradycardia-Causing Agents
- Calcium-Regulating Hormones and Agents
- Cardiovascular Agents
- Central Nervous System Agents
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Substrates
- Fenamates
- Hormone Antagonists
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Membrane Transport Modulators
- Migraine Disorders, drug therapy
- Musculo-Skeletal System
- Nephrotoxic agents
- Neurotransmitter Agents
- Non COX-2 selective NSAIDS
- Peripheral Nervous System Agents
- Prostaglandin Antagonists
- Sensory System Agents
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as aminobenzoic acids. These are benzoic acids containing an amine group attached to the benzene moiety.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Benzene and substituted derivatives
- Sub Class
- Benzoic acids and derivatives
- Direct Parent
- Aminobenzoic acids
- Alternative Parents
- Benzoic acids / Aminotoluenes / Aniline and substituted anilines / Benzoyl derivatives / Chlorobenzenes / Aryl chlorides / Vinylogous amides / Amino acids / Secondary amines / Monocarboxylic acids and derivatives show 6 more
- Substituents
- Amine / Amino acid / Amino acid or derivatives / Aminobenzoic acid / Aminotoluene / Aniline or substituted anilines / Aromatic homomonocyclic compound / Aryl chloride / Aryl halide / Benzoic acid show 18 more
- Molecular Framework
- Aromatic homomonocyclic compounds
- External Descriptors
- organochlorine compound, secondary amino compound, aminobenzoic acid (CHEBI:32243)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 3G943U18KM
- CAS number
- 13710-19-5
- InChI Key
- YEZNLOUZAIOMLT-UHFFFAOYSA-N
- InChI
- InChI=1S/C14H12ClNO2/c1-9-11(15)6-4-8-12(9)16-13-7-3-2-5-10(13)14(17)18/h2-8,16H,1H3,(H,17,18)
- IUPAC Name
- 2-[(3-chloro-2-methylphenyl)amino]benzoic acid
- SMILES
- CC1=C(Cl)C=CC=C1NC1=CC=CC=C1C(O)=O
References
- General References
- Pentikainen PJ, Neuvonen PJ, Backman C: Human pharmacokinetics of tolfenamic acid, a new anti-inflammatory agent. Eur J Clin Pharmacol. 1981;19(5):359-65. [Article]
- Tokola RA, Neuvonen PJ: Effects of migraine attack and metoclopramide on the absorption of tolfenamic acid. Br J Clin Pharmacol. 1984 Jan;17(1):67-75. [Article]
- Lees P, McKellar QA, Foot R, Gettinby G: Pharmacodynamics and pharmacokinetics of tolfenamic acid in ruminating calves: evaluation in models of acute inflammation. Vet J. 1998 May;155(3):275-88. [Article]
- McKellar QA, Lees P, Gettinby G: Pharmacodynamics of tolfenamic acid in dogs. Evaluation of dose response relationships. Eur J Pharmacol. 1994 Mar 3;253(3):191-200. [Article]
- Kankaanranta H, Moilanen E, Vapaatalo H: Tolfenamic acid inhibits leukotriene B4-induced chemotaxis of polymorphonuclear leukocytes in vitro. Inflammation. 1991 Apr;15(2):137-43. [Article]
- Jaussaud P, Guieu D, Bellon C, Barbier B, Lhopital MC, Sechet R, Courtot D, Toutain PL: Pharmacokinetics of tolfenamic acid in the horse. Equine Vet J Suppl. 1992 Feb;(11):69-72. [Article]
- Laznicek M, Senius KE: Protein binding of tolfenamic acid in the plasma from patients with renal and hepatic disease. Eur J Clin Pharmacol. 1986;30(5):591-6. [Article]
- Pedersen SB: Biopharmaceutical aspects of tolfenamic acid. Pharmacol Toxicol. 1994;75 Suppl 2:22-32. [Article]
- EMA [Link]
- European Journal of Chemistry [Link]
- Clotam leaflet [Link]
- EMA [Link]
- External Links
- Human Metabolome Database
- HMDB0042043
- KEGG Drug
- D01183
- PubChem Compound
- 610479
- PubChem Substance
- 310265123
- ChemSpider
- 530683
- BindingDB
- 35905
- 38377
- ChEBI
- 32243
- ChEMBL
- CHEMBL121626
- ZINC
- ZINC000000002188
- PharmGKB
- PA166049189
- PDBe Ligand
- TLF
- Wikipedia
- Tolfenamic_acid
- PDB Entries
- 4g77 / 5ikt / 6ap6 / 7g08
- MSDS
- Download (25.5 KB)
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 1 Withdrawn Treatment Pancreatic Cancer 1 1, 2 Not Yet Recruiting Treatment Progressive Supranuclear Palsy (PSP) 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral Injection, solution Intravenous - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 207ºC Deriv of anthranilic acid, related structurally to mefenamic and flufenamic acids. (1966) water solubility 1 mg/ml 'MSDS' logP 5.17 US-EPA pKa 5.11 Mefenamic acid: analytical profile. (2005) - Predicted Properties
Property Value Source Water Solubility 0.0158 mg/mL ALOGPS logP 4.64 ALOGPS logP 5.49 Chemaxon logS -4.2 ALOGPS pKa (Strongest Acidic) 3.88 Chemaxon pKa (Strongest Basic) -2.1 Chemaxon Physiological Charge -1 Chemaxon Hydrogen Acceptor Count 3 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 49.33 Å2 Chemaxon Rotatable Bond Count 3 Chemaxon Refractivity 71.65 m3·mol-1 Chemaxon Polarizability 26.46 Å3 Chemaxon Number of Rings 2 Chemaxon Bioavailability 1 Chemaxon Rule of Five No Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 161.3382564 predictedDarkChem Lite v0.1.0 [M-H]- 150.7658 predictedDeepCCS 1.0 (2019) [M+H]+ 161.1950564 predictedDarkChem Lite v0.1.0 [M+H]+ 153.12381 predictedDeepCCS 1.0 (2019) [M+Na]+ 161.4255564 predictedDarkChem Lite v0.1.0 [M+Na]+ 159.21704 predictedDeepCCS 1.0 (2019)
Targets
![](https://go.drugbank.com/assets/locked/DrugTargets2-682eb846d210ae4bf33ca03febccfb57bb1c61318e699b729e5df4dfab2c5b67.png)
- Kind
- Protein
- Organism
- Humans
- 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
- Lees P, McKellar QA, Foot R, Gettinby G: Pharmacodynamics and pharmacokinetics of tolfenamic acid in ruminating calves: evaluation in models of acute inflammation. Vet J. 1998 May;155(3):275-88. [Article]
- McKellar QA, Lees P, Gettinby G: Pharmacodynamics of tolfenamic acid in dogs. Evaluation of dose response relationships. Eur J Pharmacol. 1994 Mar 3;253(3):191-200. [Article]
- Tokola RA, Neuvonen PJ: Effects of migraine attack and metoclopramide on the absorption of tolfenamic acid. Br J Clin Pharmacol. 1984 Jan;17(1):67-75. [Article]
- Kind
- Protein
- Organism
- Humans
- 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
- Lees P, McKellar QA, Foot R, Gettinby G: Pharmacodynamics and pharmacokinetics of tolfenamic acid in ruminating calves: evaluation in models of acute inflammation. Vet J. 1998 May;155(3):275-88. [Article]
- McKellar QA, Lees P, Gettinby G: Pharmacodynamics of tolfenamic acid in dogs. Evaluation of dose response relationships. Eur J Pharmacol. 1994 Mar 3;253(3):191-200. [Article]
- Tokola RA, Neuvonen PJ: Effects of migraine attack and metoclopramide on the absorption of tolfenamic acid. Br J Clin Pharmacol. 1984 Jan;17(1):67-75. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Vitamin d3 25-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 performs a variety of oxidation react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Uesawa Y, Takeuchi T, Mohri K: Integrated analysis on the physicochemical properties of dihydropyridine calcium channel blockers in grapefruit juice interactions. Curr Pharm Biotechnol. 2012 Jul;13(9):1705-17. [Article]
Drug created at October 21, 2015 16:21 / Updated at August 28, 2021 08:41