TOLMETIN

First approved in 1976

Details

Stereochemistry	ACHIRAL
Molecular Formula	C15H15NO3
Molecular Weight	257.2845
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CN1C(CC(O)=O)=CC=C1C(=O)C2=CC=C(C)C=C2

InChI

InChIKey=UPSPUYADGBWSHF-UHFFFAOYSA-N

InChI=1S/C15H15NO3/c1-10-3-5-11(6-4-10)15(19)13-8-7-12(16(13)2)9-14(17)18/h3-8H,9H2,1-2H3,(H,17,18)

HIDE SMILES / InChI

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/018084s052,017628s068lbl.pdf | https://www.drugbank.ca/drugs/DB00500

Tolmetin is a nonsteroidal anti-inflammatory agent. It was marketed as Tolectin in USA. TOLECTIN (tolmetin sodium) is indicated for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis. TOLECTIN is indicated in the treatment of acute flares and the long-term management of the chronic disease. TOLECTIN is also indicated for treatment of juvenile rheumatoid arthritis. The mode of action of tolmetin is not known. However, studies in laboratory animals and man have demonstrated that the anti-inflammatory action of tolmetin is not due to pituitary-adrenal stimulation. Tolmetin inhibits prostaglandin synthetase in vitro and lowers the plasma level of prostaglandin E in man. This reduction in prostaglandin synthesis may be responsible for the anti-inflammatory action.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Cyclooxygenase-1 127 Target ID: CHEMBL221 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10465690 \| http://www.genome.jp/dbget-bin/www_bget?D02355	Inhibitor 8297	0.35 µM [IC50]
Cyclooxygenase-2 196 Target ID: CHEMBL230 Sources: http://www.genome.jp/dbget-bin/www_bget?D02355 \| https://www.drugbank.ca/drugs/DB00500	Inhibitor 8297	0.82 µM [IC50]
Cyclooxygenase 89 Target ID: CHEMBL2094253 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16396699\|https://adisinsight.springer.com/drugs/800002179	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Rheumatoid arthritis 316 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/018084s052,017628s068lbl.pdf	Primary		Approved 8429	Tolmetin sodium Approved Use Carefully consider the potential benefits and risks of tolmetin sodium capsules and other treatment options before deciding to use tolmetin sodium capsules. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). Tolmetin sodium capsules are indicated for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis. Tolmetin sodium capsules are indicated in the treatment of acute flares and the long-term management of the chronic disease. Tolmetin sodium capsules are also indicated for treatment of juvenile rheumatoid arthritis. The safety and effectiveness of tolmetin sodium capsules have not been established in pediatric patients under 2 years of age. Launch Date 1976
Osteoarthritis 157 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/018084s052,017628s068lbl.pdf	Primary		Approved 8429	Tolmetin sodium Approved Use Carefully consider the potential benefits and risks of tolmetin sodium capsules and other treatment options before deciding to use tolmetin sodium capsules. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). Tolmetin sodium capsules are indicated for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis. Tolmetin sodium capsules are indicated in the treatment of acute flares and the long-term management of the chronic disease. Tolmetin sodium capsules are also indicated for treatment of juvenile rheumatoid arthritis. The safety and effectiveness of tolmetin sodium capsules have not been established in pediatric patients under 2 years of age. Launch Date 1976

C_max

Value	Dose	Co-administered	Analyte	Population
29.3 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1126116/	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:		TOLMETIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
50.5 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1126116/	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:		TOLMETIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
0.83 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1126116/	300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered:		TOLMETIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

Doses

Dose	Population	Adverse events
400 mg 3 times / day steady, oral (starting) Dose: 400 mg, 3 times / day Route: oral Route: steady Dose: 400 mg, 3 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/018084s052,017628s068lbl.pdf	unhealthy, adults n = 800 Health Status: unhealthy Condition: rheumatoid arthritis and osteoarthritis Age Group: adults Population Size: 800 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/018084s052,017628s068lbl.pdf	Other AEs: Nausea, Dyspepsia... Other AEs: Nausea (11%) Dyspepsia (3-9) Distress gastrointestinal (3-9) Abdominal pain (3-9) Diarrhea (3-9) Flatulence (3-9) Vomiting (3-9) Constipation (1-3) Gastritis (1-3) Peptic ulcer (1-3) Headache (3-9) Asthenia (3-9) Chest pain (1-3) Blood pressure increased (3-9) Edema (3-9) Dizziness (3-9) Drowsiness (3-9) Depression (1-3) Weight gain (3-9) Weight loss (3-9) Skin irritation (1-3) Tinnitus (1-3) Visual disturbance (1-3) Blood urea nitrogen increased (1-3) Urinary tract infection (1-3) Gastrointestinal ulcer bleeding (<1%) Bleeding gastrointestinal (<1%) Perforation (<1%) Glossitis (<1%) Stomatitis (<1%) Hepatitis (<1%) Function liver abnormal (<1%) Anaphylactoid reaction (<1%) Fever (<1%) Lymphadenopathy (<1%) Serum sickness (<1%) Hemolytic anemia (<1%) Thrombocytopenia (<1%) Granulocytopenia (<1%) Agranulocytosis (<1%) Urticaria (<1%) Purpura (<1%) Erythema multiforme (<1%) Toxic epidermal necrolysis (<1%) Hematuria (<1%) Proteinuria (<1%) Dysuria (<1%) Renal failure (<1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/018084s052,017628s068lbl.pdf

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
MRP2 383 MRP4 204	UGT 192

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
MRP4 238	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/17005917/	yes [IC50 20.5 uM]
MRP2 475	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/17005917/	yes [IC50 494 uM]

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
CYP3A4 1737	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/16251255/	yes
UGT 192	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/31839590/	yes

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:71941	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:71941
ChemicalBook	CB2875183	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB2875183
ChemicalBook	CB84634335	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB84634335
ZINC	ZINC000000002191	http://zinc15.docking.org/substances/ZINC000000002191
eMolecules	5753460	https://www.emolecules.com/cgi-bin/more?vid=5753460

PubMed

Title	Date	PubMed
Immune hemolytic anemia associated with tolmetin and suprofen.	1989 Sep	2773031
Multisystem failure and hepatic microvesicular fatty metamorphosis associated with tolmetin ingestion.	1991 Aug	1863194
Determination of nonsteroidal anti-inflammatory drugs in biological fluids by automatic on-line integration of solid-phase extraction and capillary electrophoresis.	2001 Feb	11258759
Dipeptidyl peptidase IV is a target for covalent adduct formation with the acyl glucuronide metabolite of the anti-inflammatory drug zomepirac.	2001 Jan 5	11205870
Screening procedure for detection of non-steroidal anti-inflammatory drugs and their metabolites in urine as part of a systematic toxicological analysis procedure for acidic drugs and poisons by gas chromatography-mass spectrometry after extractive methylation.	2001 May-Jun	11386636
Inhibition of proliferation of HT-29 colon adenocarcinoma cells by carboxylate NSAIDs and their acyl glucuronides.	2001 Nov 21	11764005
New hydrogel matrices containing an anti-inflammatory agent. Evaluation of in vitro release and photoprotective activity.	2002 Jan	11761174
Effect of experimental hypoalbuminemia on the plasma protein binding of tolmetin.	2002 Jul 19	12088761
Gastroprotective effects of amtolmetin guacyl: a new non-steroidal anti-inflammatory drug that activates inducible gastric nitric oxide synthase.	2002 Jun	12132787
Detection and disposition of tolmetin in the horse.	2003 Mar 26	12644199
Identification of coenzyme A-related tolmetin metabolites in rats: relationship with reactive drug metabolites.	2003 May	12746110
Identification of zomepirac-S-acyl-glutathione in vitro in incubations with rat hepatocytes and in vivo in rat bile.	2003 Nov	14570776
Treatment of congenital nephrogenic diabetes insipidus by hydrochlorothiazide and cyclooxygenase-2 inhibitor.	2003 Oct	12883974
Prostaglandin levels in seminal plasma and sperm extracts of the domestic turkey, and the effects of cyclooxygenase inhibitors on sperm mobility.	2003 Oct 9	14613550
Nondestructive measurements of the compact strength and the particle-size distribution after milling of roller compacted powders by near-infrared spectroscopy.	2004 Apr	14999740
Micellar electrokinetic chromatography for the simultaneous determination of ketorolac tromethamine and its impurities. Multivariate optimization and validation.	2004 Apr 2	15065803
Photolysis of NSAIDs. IV. Photoproducts of zomepirac determined by LC-ESI-MS.	2004 Dec	15386573
In vitro reactivity of carboxylic acid-CoA thioesters with glutathione.	2004 Jan	14727921
Spectroscopic behavior of copper complexes of nonsteroidal anti-inflammatory drugs.	2004 May-Jun 5	15137108
Hydrogen peroxide scavenging activity by non-steroidal anti-inflammatory drugs.	2005 Apr 29	15808884
Kinetic studies on the intramolecular acyl migration of beta-1-O-acyl glucuronides: application to the glucuronides of (R)- and (S)-ketoprofen, (R)- and (S)-hydroxy-ketoprofen metabolites, and tolmetin by 1H-NMR spectroscopy.	2005 Jul	16316930
Prediction of genotoxicity of chemical compounds by statistical learning methods.	2005 Jun	15962942
In vitro and in vivo studies on acyl-coenzyme A-dependent bioactivation of zomepirac in rats.	2005 Nov	16300382
I almost crossed over.	2005 Oct	17094512
Anti-inflammatory and immunosuppressive drugs and reproduction.	2006	16712713
An exploratory theoretical elucidation on the peroxyl-radical-scavenging mechanism and structure-activity relationship of nonsteroidal anti-inflammatory drugs.	2006 Jun 15	16600595
Celosomy is associated with prenatal exposure to cyclooxygenase inhibitors.	2006 Mar	16460959
In vivo effects of amtolmetin guacyl on lipid peroxidation and antioxidant defence systems. Comparison with non-selective and COX-2 selective NSAIDs.	2007 Apr	17391279
In vivo effects of amtolmetin guacyl on lipid peroxidation and antioxidant defence systems in different models of gastrointestinal injury.	2007 Jan	17199877
Interaction of nonsteroidal anti-inflammatory drugs with multidrug resistance protein (MRP) 2/ABCC2- and MRP4/ABCC4-mediated methotrexate transport.	2007 Jan	17005917
Polyproline-rod approach to isolating protein targets of bioactive small molecules: isolation of a new target of indomethacin.	2007 Jan 31	17243824
Determination of degradation pathways and kinetics of acyl glucuronides by NMR spectroscopy.	2007 Jun	17536843
Improving adherence to medical regimens for juvenile rheumatoid arthritis.	2007 May 18	17550635
Role of biotransformation studies in minimizing metabolism-related liabilities in drug discovery.	2008	18446518
Topical ocular delivery of NSAIDs.	2008 Jun	18437583
Entrapment of ketorolac tromethamine in polymeric vehicle for controlled drug delivery.	2009 Nov	20376226
Maternal toxicity of nonsteroidal anti-inflammatory drugs as an important factor affecting prenatal development.	2009 Sep	19379806
Friedel-Crafts acylation of pyrroles and indoles using 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) as a nucleophilic catalyst.	2010 Dec 17	21077631
Nonsteroidal Anti-Inflammatory Drugs: A survey of practices and concerns of pediatric medical and surgical specialists and a summary of available safety data.	2010 Feb 4	20181090
Diclofenac hypersensitivity: antibody responses to the parent drug and relevant metabolites.	2010 Oct 28	21060839
Identification of old drugs as potential inhibitors of HIV-1 integrase - human LEDGF/p75 interaction via molecular docking.	2012 Dec	22733274
A correlation between the in vitro drug toxicity of drugs to cell lines that express human P450s and their propensity to cause liver injury in humans.	2014 Jan	24085192
Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis.	2015 May 18	25811541

Patents

Sample Use Guides

In Vivo Use Guide

For the relief of rheumatoid arthritis or osteoarthritis, the recommended starting dose for adults is 400 mg three times daily (1200 mg daily), preferably including a dose on arising and a dose at bedtime. To achieve optimal therapeutic effect the dose should be adjusted according to the patient’s response after one or two weeks. Control is 15 usually achieved at doses of 600-1800 mg daily in divided doses (generally t.i.d.). Doses larger than 1800 mg/day have not been studied and are not recommended.

Route of Administration: Oral

In Vitro Use Guide

Tolmetin inhibited the activity of human COX-1 and -2 with IC50 values of 0.35 and 0.82 uM, respectively

Name

Type

Language

TOLMETIN

Official Name

English

TOLMETIN [MI]

Common Name

English

TOLMETIN [VANDF]

Common Name

English

TOLMETIN [JAN]

Common Name

English

MCN-2559

Code

English

Tolmetin [WHO-DD]

Common Name

English

tolmetin [INN]

Common Name

English

TOLMETIN [HSDB]

Common Name

English

TOLMETIN [USAN]

Common Name

English

Classification Tree Code System Code

NDF-RT

N0000000160