TOLMETIN SODIUM

First approved in 1976

Details

Stereochemistry	ACHIRAL
Molecular Formula	C15H14NO3.Na.2H2O
Molecular Weight	315.2969
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

O.O.[Na+].CN1C(CC([O-])=O)=CC=C1C(=O)C2=CC=C(C)C=C2

InChI

InChIKey=QQILXENAYPUNEA-UHFFFAOYSA-M

InChI=1S/C15H15NO3.Na.2H2O/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);;2*1H2/q;+1;;/p-1

HIDE SMILES / InChI

Molecular Formula	H2O
Molecular Weight	18.0153
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Molecular Formula	C15H15NO3
Molecular Weight	257.2845
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Molecular Formula	Na
Molecular Weight	22.9898
Charge	1
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

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 1.96473602E11
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 1.96473602E11

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
A population model for tolmetin pharmacokinetics in rats considering saturable elimination.	2001	11793960
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
Retrospective analysis of drug-induced urticaria and angioedema: a survey of 2287 patients.	2001 Nov	11792017
Three new vanadyl(IV) complexes with non-steroidal anti-inflammatory drugs (Ibuprofen, Naproxen and Tolmetin). Bioactivity on osteoblast-like cells in culture.	2002 Jan 1	11750030
Effect of experimental hypoalbuminemia on the plasma protein binding of tolmetin.	2002 Jul 19	12088761
Tolmetin and salicylate therapy in acute rheumatic fever: Comparison of clinical efficacy and side-effects.	2003 Dec	14651540
Detection and disposition of tolmetin in the horse.	2003 Mar 26	12644199
Alkenyl C-H insertion of iodonium ylides into pyrroles: studies toward the total syntheses of tolmetin and amtolmetin guacil.	2003 May 1	12713311
Developmental toxicity evaluation of ibuprofen and tolmetin administered in triple daily doses to Wistar CRL:(WI)WUBR rats.	2004 Oct	15505808
Sample pretreatment and determination of non steroidal anti-inflammatory drugs (NSAIDs) in pharmaceutical formulations and biological samples (blood, plasma, erythrocytes) by HPLC-UV-MS and micro-HPLC.	2005	15777213
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
A competitive low-affinity binding model for determining the mutual and specific sites of two ligands on protein.	2005 Jul 15	15967285
Prediction of genotoxicity of chemical compounds by statistical learning methods.	2005 Jun	15962942
Evidence for the bioactivation of zomepirac and tolmetin by an oxidative pathway: identification of glutathione adducts in vitro in human liver microsomes and in vivo in rats.	2006 Jan	16251255
An exploratory theoretical elucidation on the peroxyl-radical-scavenging mechanism and structure-activity relationship of nonsteroidal anti-inflammatory drugs.	2006 Jun 15	16600595
Scavenging of reactive oxygen species by some nonsteroidal anti-inflammatory drugs and fenofibrate.	2006 Jun 5	16245331
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
One center's experience: the serology and drugs associated with drug-induced immune hemolytic anemia--a new paradigm.	2007 Apr	17381629
Potential antioxidant activity of celecoxib and amtolmetin guacyl: in vitro studies.	2007 Jan	17199871
A simple in vitro model to study the stability of acylglucuronides.	2007 Jan-Feb	16713308
Non-steroidal anti-inflammatory agents, tolmetin and sulindac attenuate quinolinic acid (QA)-induced oxidative stress in primary hippocampal neurons and reduce QA-induced spatial reference memory deficits in male Wistar rats.	2007 Mar 20	17266991
Studies on the metabolism of tolmetin to the chemically reactive acyl-coenzyme A thioester intermediate in rats.	2007 May	17303625
Idiopathic chondrolysis of the hip: a case report.	2007 Oct	18019924
Cyclooxygenase inhibitors affect bone mineralization in rat fetuses.	2008	17992008
Topical ocular delivery of NSAIDs.	2008 Jun	18437583
Drug-organic electrolyte complexes as controlled release systems.	2009 Jan	18991061
A study of the intermolecular interactions of tolmetin/N-acetyl-L-tyrosine ethyl ester complex.	2009 Jun	19181568
Sequential injection system for phospholipase A2 activity evaluation: studies on liposomes using an environment-sensitive fluorescent probe.	2009 Sep 15	19615520
Accuracy of rapid urease test in diagnosing Helicobacter pylori infection in patients using NSAIDs.	2010 Apr-Jun	20339181
Development of theophylline floating microballoons using cellulose acetate butyrate and/or Eudragit RL 100 polymers with different permeability characteristics.	2010 Jan	21589766
Evaluation of Wound Healing Potential of Bauhinia purpurea Leaf Extracts in Rats.	2010 Jan	20582204
Effect of formulation and processing variables on the characteristics of tolmetin microspheres prepared by double emulsion solvent diffusion method.	2010 Jan	20582193
Unusual interleukin-1 and -6 expression in fetal cartilage is associated with placental abnormalities.	2010 Jan 1	20529813
Determination of actarit from human plasma for bioequivalence studies.	2010 Nov	21969744
Validation and clinical application of an LC-ESI-MS/MS method for simultaneous determination of tolmetin and MED5, the metabolites of amtolmetin guacil in human plasma.	2010 Oct	20853464
Diclofenac hypersensitivity: antibody responses to the parent drug and relevant metabolites.	2010 Oct 28	21060839
Effect of ketorolac and diclofenac on the impairment of endothelium-dependent relaxation induced by reactive oxygen species in rabbit abdominal aorta.	2010 Sep	20877705
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

Substance Class	Chemical Created by `admin` on `Fri Dec 15 15:15:22 UTC 2023` Edited by `admin` on `Fri Dec 15 15:15:22 UTC 2023`
Record UNII	02N1TZF99F
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

TOLMETIN SODIUM

Official Name

English

TOLMETIN SODIUM [USP-RS]

Common Name

English

TOLMETIN SODIUM [USP MONOGRAPH]

Common Name

English

TOLMETIN SODIUM [MART.]

Common Name

English

TOLMETIN SODIUM SALT DIHYDRATE

Common Name

English

TOLMETIN SODIUM SALT DIHYDRATE [MI]

Common Name

English

TOLECTIN

Brand Name

English

1H-PYRROLE-2-ACETIC ACID, 1-METHYL-5-(4-METHYLBENZOYL)-, SODIUM SALT, DIHYDRATE

Common Name

English

TOLMETIN SODIUM [VANDF]

Common Name

English

TOLMETIN SODIUM [USAN]

Common Name

English

MCN-2559-21-98

Code

English

TOLMETIN SODIUM [ORANGE BOOK]

Common Name

English

TOLMETIN SODIUM [JAN]

Common Name

English

TOLMETIN SODIUM DIHYDRATE

Common Name

English

SODIUM 1-METHYL-5-P-TOLUOYLPYRROLE-2-ACETATE DIHYDRATE

Common Name

English

1H-PYRROLE-2-ACETIC ACID, 1-METHYL-5-(4-METHYLBENZOYL)-, SODIUM SALT, HYDRATE (1:1:2)

Common Name

English

NSC-757341

Code

English

Classification Tree Code System Code

NCI_THESAURUS

C257