Identification

Name
Tolfenamic Acid
Accession Number
DB09216
Type
Small Molecule
Groups
Approved, Investigational
Description

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]

Structure
Thumb
Synonyms
Not Available
International/Other Brands
Clotam (GEA Farmaceutisk Fabrik)
Categories
UNII
3G943U18KM
CAS number
13710-19-5
Weight
Average: 261.704
Monoisotopic: 261.05565634
Chemical Formula
C14H12ClNO2
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

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]

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]

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

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]

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]

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 Tolfenamic Acid is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding and hemorrhage can be increased when Tolfenamic Acid is combined with (S)-Warfarin.
4-hydroxycoumarinThe risk or severity of bleeding and hemorrhage can be increased when Tolfenamic Acid is combined with 4-hydroxycoumarin.
AbafunginThe therapeutic efficacy of Abafungin can be increased when used in combination with Tolfenamic Acid.
AbciximabThe risk or severity of bleeding and hemorrhage can be increased when Tolfenamic Acid is combined with Abciximab.
AcebutololTolfenamic Acid may decrease the antihypertensive activities of Acebutolol.
AceclofenacThe risk or severity of adverse effects can be increased when Aceclofenac is combined with Tolfenamic Acid.
AcemetacinThe risk or severity of adverse effects can be increased when Tolfenamic Acid is combined with Acemetacin.
AcenocoumarolThe risk or severity of bleeding and hemorrhage can be increased when Tolfenamic Acid is combined with Acenocoumarol.
AcepromazineThe risk or severity of hypotension can be increased when Acepromazine is combined with Tolfenamic Acid.
Food Interactions
Not Available

References

General References
  1. 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. [PubMed:7238564]
  2. 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. [PubMed:6691890]
  3. 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. [PubMed:9638074]
  4. 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. [PubMed:8200415]
  5. 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. [PubMed:1649132]
  6. 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. [PubMed:9109966]
  7. 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. [PubMed:3758148]
  8. Pedersen SB: Biopharmaceutical aspects of tolfenamic acid. Pharmacol Toxicol. 1994;75 Suppl 2:22-32. [PubMed:7816776]
  9. EMA [Link]
  10. European Journal of Chemistry [Link]
  11. Clotam leaflet [Link]
  12. EMA [Link]
External Links
Human Metabolome Database
HMDB0042043
KEGG Drug
D01183
PubChem Compound
610479
PubChem Substance
310265123
ChemSpider
530683
BindingDB
35905
ChEBI
32243
ChEMBL
CHEMBL121626
PharmGKB
PA166049189
HET
TLF
Wikipedia
Tolfenamic_acid
ATC Codes
M01AG02 — Tolfenamic acid
PDB Entries
4g77 / 5ikt / 6ap6
MSDS
Download (25.5 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)207ºC Deriv of anthranilic acid, related structurally to mefenamic and flufenamic acids. (1966)
water solubility1 mg/ml'MSDS'
logP5.17US-EPA
pKa5.11Mefenamic acid: analytical profile. (2005)
Predicted Properties
PropertyValueSource
Water Solubility0.0158 mg/mLALOGPS
logP4.64ALOGPS
logP5.49ChemAxon
logS-4.2ALOGPS
pKa (Strongest Acidic)3.88ChemAxon
pKa (Strongest Basic)-2.1ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area49.33 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity71.65 m3·mol-1ChemAxon
Polarizability26.46 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
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
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0006-1290000000-90928e5629bf0b4869e8
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0a59-2790000000-175a0f838779d665e3db

Taxonomy

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
Aminobenzoic acid / Benzoic acid / Benzoyl / Aniline or substituted anilines / Aminotoluene / Chlorobenzene / Halobenzene / Toluene / Aryl chloride / Aryl halide
show 18 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
organochlorine compound, secondary amino compound, aminobenzoic acid (CHEBI:32243)

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. 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. [PubMed:9638074]
  2. 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. [PubMed:8200415]
  3. 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. [PubMed:6691890]
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. 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. [PubMed:9638074]
  2. 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. [PubMed:8200415]
  3. 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. [PubMed:6691890]

Enzymes

Kind
Protein
Organism
Human
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
  1. 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. [PubMed:22039822]

Drug created on October 21, 2015 10:21 / Updated on October 01, 2018 14:48