AMTOLMETIN GUACIL

First approved in 1976

Details

Stereochemistry	ACHIRAL
Molecular Formula	C24H24N2O5
Molecular Weight	420.4578
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

COC1=C(OC(=O)CNC(=O)CC2=CC=C(N2C)C(=O)C3=CC=C(C)C=C3)C=CC=C1

InChI

InChIKey=CWJNMKKMGIAGDK-UHFFFAOYSA-N

InChI=1S/C24H24N2O5/c1-16-8-10-17(11-9-16)24(29)19-13-12-18(26(19)2)14-22(27)25-15-23(28)31-21-7-5-4-6-20(21)30-3/h4-13H,14-15H2,1-3H3,(H,25,27)

HIDE SMILES / InChI

Molecular Formula	C24H24N2O5
Molecular Weight	420.4578
Charge	0
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
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
Naproxen-induced recurrent aseptic meningitis.	1991 Nov	1763533
In vitro and in vivo studies on acyl-coenzyme A-dependent bioactivation of zomepirac in rats.	2005 Nov	16300382
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
Scavenging of reactive oxygen species by some nonsteroidal anti-inflammatory drugs and fenofibrate.	2006 Jun 5	16245331
Celosomy is associated with prenatal exposure to cyclooxygenase inhibitors.	2006 Mar	16460959
Non-steroidal anti-inflammatory agents, tolmetin and sulindac, attenuate oxidative stress in rat brain homogenate and reduce quinolinic acid-induced neurodegeneration in rat hippocampal neurons.	2006 Sep	16850258
One center's experience: the serology and drugs associated with drug-induced immune hemolytic anemia--a new paradigm.	2007 Apr	17381629
Determination of non-steroidal anti-inflammatory drugs in urine by combining an immobilized carboxylated carbon nanotubes minicolumn for solid-phase extraction with capillary electrophoresis-mass spectrometry.	2007 Aug 3	17300791
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
A peripatetic pediatrician's journey into pediatric rheumatology: Part II.	2007 Jun 21	17584931
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
Improving adherence to medical regimens for juvenile rheumatoid arthritis.	2007 May 18	17550635
Idiopathic chondrolysis of the hip: a case report.	2007 Oct	18019924
Singlet oxygen scavenging activity of non-steroidal anti-inflammatory drugs.	2008	18647485
Role of biotransformation studies in minimizing metabolism-related liabilities in drug discovery.	2008	18446518
Cyclooxygenase inhibitors affect bone mineralization in rat fetuses.	2008	17992008
Modulation of dopaminergic neurotransmission in rat striatum upon in vitro and in vivo diclofenac treatment.	2008 Apr	18036194
Ionic liquid-based dynamic liquid-phase microextraction: application to the determination of anti-inflammatory drugs in urine samples.	2008 Aug 15	18632109
Topical ocular delivery of NSAIDs.	2008 Jun	18437583
The effect of piroxicam on the formation of postoperative, intraabdominal adhesion in rats.	2008 Oct	19568538
A novel high-throughput screening assay for putative antidiabetic agents through PPARalpha interactions.	2008 Oct	18812576
Methotrexate for the treatment of juvenile idiopathic arthritis: process to approval for JIA indication in Japan.	2009	18815725
Glycerolysis of acyl glucuronides as an artifact of in vitro drug metabolism incubations.	2009 Aug	19439485
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
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
Sequential injection system for phospholipase A2 activity evaluation: studies on liposomes using an environment-sensitive fluorescent probe.	2009 Sep 15	19615520
An evaluation of the utility of routine laboratory monitoring of juvenile idiopathic arthritis (JIA) patients using non-steroidal anti-inflammatory drugs (NSAIDs): a retrospective review.	2010 Apr 14	20398286
Accuracy of rapid urease test in diagnosing Helicobacter pylori infection in patients using NSAIDs.	2010 Apr-Jun	20339181
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
Selected pharmacokinetic issues of the use of antiepileptic drugs and parenteral nutrition in critically ill patients.	2010 Dec 31	21194458
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
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
Control of encapsulation efficiency in polymeric microparticle system of tolmetin.	2010 Jan-Feb	19505209
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 15:37:06 UTC 2023` Edited by `admin` on `Fri Dec 15 15:37:06 UTC 2023`
Record UNII	323A00CRO9
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

AMTOLMETIN GUACIL

Official Name

English

ST-679

Code

English

Amtolmetin guacil [WHO-DD]

Common Name

English

ARTROMED

Brand Name

English

AMTOLMETIN GUACIL [MART.]

Common Name

English

ST 679

Code

English

FINRID

Brand Name

English

AMTOLMETIN GUACIL [MI]

Common Name

English

AMTOLMETIN GUACYL

Common Name

English

amtolmetin guacil [INN]

Common Name

English

N-((1-METHYL-5-P-TOLUOYLPYRROL-2-YL)ACETYL)GLYCINE O-METHOXYPHENYL ESTER

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C257