Human COX-1 0.35 μM (IC50) Human COX-2 0.82 μM (IC50)

Rat brain homogenate lipid peroxidation is not inhibited by tolmetin (0.25 mM). In rat brain homogenate, tolmetin (0.25, 0.5, 0.75, and 1 mM) exhibits radical scavenging properties without producing superoxide anion[3]. Tolmetin (0.001-100 μM) exhibits dose-dependent anticancer activity against the HT-29 colon cancer cell line[4]. Osteoblast growth is not affected by tolmetin (0-100 μM)[5].

In male Wistar rats weighing 180-200 g, tolmetin (30,100 mg/kg; gavage; single dose or twice daily for 3 and 14 days) exhibits a peak ulcerogenic impact four hours after the single dosage and potently diminishes after three and fourteen days of recurrent administration. At 100 mg/kg, tolmetin produces stomach lesions[2]. Pre-treatment with tolmetin (5 mg/kg twice day for 5 days) significantly reduces the neurotoxicity caused by quinolinic acid (QA)[3].

Absorption, Distribution and Excretion
Rapidly and almost completely absorbed with peak plasma levels being reached within 30-60 minutes after an oral therapeutic dose.
THE DRUG IS RAPIDLY ABSORBED AFTER ORAL ADMIN, PEAK PLASMA LEVELS OCCUR IN 30 TO 60 MIN. IT IS EXCRETED LARGELY IN URINE, PRIMARILY AS CONJUGATES OR METABOLITES. ITS PLASMA HALF-LIFE IS APPROX 1 HR. /TOLMETIN SODIUM/
GI ABSORPTION IS ABOUT 90% OR GREATER...WITH PEAK LEVELS WITHIN 20-60 MIN FOR TOLMETIN... PROTEIN BINDING IS EXTENSIVE, BEING 90% OR GREATER... HEPATIC BIOTRANSFORMATION & RENAL EXCRETION WITH SOME FECAL EXCRETION OF METABOLITES ARE THE MEANS OF ELIMINATION. /TOLMETIN SODIUM/
TOLMETIN IS RAPIDLY & COMPLETELY ABSORBED FOLLOWING ORAL ADMIN TO MAN, & CONCN ACHIEVED IN PLASMA ARE NOT REDUCED BY CONCOMITANT ADMIN OF GASTRIC ANTACIDS. PEAK CONCN ARE ACHIEVED 20-60 MIN AFTER ORAL ADMIN, & T/2 IN PLASMA IS BETWEEN 1 & 3 HR.
AFTER ABSORPTION, TOLMETIN IS EXTENSIVELY (99%) BOUND TO PLASMA PROTEINS. VIRTUALLY ALL OF THE DRUG CAN BE RECOVERED IN URINE AFTER 24 HR; SOME IS UNCHANGED (17%), BUT MOST IS CONJUGATED (10%) OR OTHERWISE METABOLIZED. THE MAJOR METABOLITE TRANSFORMATION IS DECARBOXYLATION.
TOLMETIN SODIUM WAS RAPIDLY & COMPLETELY ABSORBED (PEAK TIME, 20-60 MIN) & ELIMINATED RAPIDLY FROM PLASMA WITH BIPHASIC DECAY CURVE & ELIMINATION T/2 OF APPROX 2.1 HR.

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Metabolism / Metabolites
Essentially all of the administered dose is recovered in the urine in 24 hours either as an inactive oxidative metabolite or as conjugates of tolmetin.
URINE METABOLITES 1-METHYL-5-(4-CARBOXYBENZOYL)-1H-PYRROLE-2-ACETIC ACID & TOLMETIN GLUCURONIDE NOTED AFTER TOLMETIN SODIUM.
Tolmetin has known human metabolites that include Tolmetin glucuronide.

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Biological Half-Life
Biphasic elimination from the plasma consisting of a rapid phase with a half-life of one to 2 hours followed by a slower phase with a half-life of about 5 hours.

Hepatotoxicity
Up to 5% of patients taking tolmetin chronically experience at least transient serum aminotransferase elevations. These may resolve even with drug continuation. Marked aminotransferase elevations (>3 fold elevated) occur in
Likelihood score: D (possible, rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because of the low levels of tolmetin in breastmilk and its short half-life, it is unlikely to adversely affect the breastfed infant. However, because there is no published experience with breastfeeding during tolmetin use, other agents may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Interactions
PT RECEIVING CORTICOSTEROID OR GOLD THERAPY OBTAINED GREATER RELIEF OF SYMPTOMS WHEN TOLMETIN WAS ADDED TO THE REGIMEN, & THERE WAS EVIDENCE THAT TOLMETIN HAD A STEROID-SPARING EFFECT. /TOLMETIN SODIUM/
CONCOMITANT ADMIN OF TOLMETIN & ACETAMINOPHEN PRODUCED A GREATER IMPROVEMENT IN SYMPTOMS THAN WITH TOLMETIN ALONE, BUT FURTHER STUDIES ARE NEEDED TO SUBSTANTIATE THIS EFFECT. /TOLMETIN SODIUM/
CONCOMITANT ASPIRIN REDUCES PLASMA LEVELS OF TOLMETIN BY ABOUT 20%, BUT THE INTERACTION PROBABLY IS NOT CLINICALLY IMPORTANT. /TOLMETIN SODIUM/
IN DOGS, PROSTAGLANDIN SYNTHETASE INHIBITORS INDOMETHACIN & TOLMETIN BLOCKED FUROSEMIDE-INDUCED INCR IN RENIN SECRETION WHETHER FUROSEMIDE WAS GIVEN IV OR INTO RENAL ARTERY.
DESPITE ITS EXTENSIVE BINDING TO ALBUMIN...NO CHANGE IN PROTHROMBIN TIME WHEN WARFARIN & TOLMETIN WERE GIVEN TOGETHER.

[1]. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7563-8.

[2]. Synthesis and anticancer activity of some novel tolmetin thiosemicarbazides. Marmara Pharmaceutical Journal 19(3) • April 2015.

[3]. Three new vanadyl(IV) complexes with non-steroidal anti-inflammatory drugs (Ibuprofen, Naproxen and Tolmetin). Bioactivity on osteoblast-like cells in culture. J Inorg Biochem. 2002 Jan 1;88(1):94-100.

Tolmetin is a monocarboxylic acid that is (1-methylpyrrol-2-yl)acetic acid substituted at position 5 on the pyrrole ring by a 4-methylbenzoyl group. Used in the form of its sodium salt dihydrate as a nonselective nonsteroidal anti-inflammatory drug. It has a role as a non-steroidal anti-inflammatory drug and an EC 1.14.99.1 (prostaglandin-endoperoxide synthase) inhibitor. It is a member of pyrroles, a monocarboxylic acid and an aromatic ketone. It is a conjugate acid of a tolmetin(1-).
A non-steroidal anti-inflammatory agent (anti-inflammatory agents, NON-steroidal) similar in mode of action to indomethacin.
Tolmetin is a Nonsteroidal Anti-inflammatory Drug. The mechanism of action of tolmetin is as a Cyclooxygenase Inhibitor.
Tolmetin is a nonsteroidal antiinflammatory drug (NSAID) that is available by prescription only and used for therapy of chronic arthritis. Tolmetin is associated with low rates of serum aminotransferase elevations during therapy and has been linked to rare instances of clinically apparent drug induced liver injury.
Tolmetin is an arylalkanoic acid and non-steroidal anti-inflammatory drug (NSAID) with analgesic, anti-inflammatory and antipyretic activities. Although the exact mechanism through which tolmetin exerts its effects has yet to be fully elucidated, this agent appears to inhibit the enzyme prostaglandin synthase. This prevents the formation of prostaglandins from prostaglandin precursors, including the synthesis of the inflammatory prostaglandin E2 (PGE2) from the precursor prostaglandin H2 (PGH2). This prevents prostaglandin-mediated effects, including pain, inflammation and fever.
A non-steroidal anti-inflammatory agent (ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL) similar in mode of action to INDOMETHACIN.
See also: Tolmetin Sodium (has salt form); Amtolmetin Guacil (is active moiety of).

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Drug Indication
For the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis, including the treatment of acute flares long-term management. Also for treatment of juvenile rheumatoid arthritis.
FDA Label

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Mechanism of Action
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. Tolmetin does not appear to alter the course of the underlying disease in man.
ALTHOUGH IT DIFFERS CHEMICALLY FROM ASPIRIN & OTHER NONSTEROIDAL ANTI-INFLAMMATORY AGENTS, ITS PHARMACOLOGIC PROPERTIES ARE SIMILAR. /TOLMETIN SODIUM/
...INHIBITS PROSTAGLANDIN SYNTHETASE IN VITRO. IT ALSO HAS BEEN SHOWN TO LOWER PLASMA LEVEL OF PROSTAGLANDIN E IN MAN. HOWEVER, SIGNIFICANCE OF THESE ACTIONS IN RELATION TO CLINICAL EFFECTS IS NOT KNOWN. /TOLMETIN SODIUM/

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Therapeutic Uses
Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase Inhibitors
IN SEVERAL CONTROLLED STUDIES IN PT WITH RHEUMATOID ARTHRITIS, TOLMETIN REDUCED SEVERITY OF SYMPTOMS (...JOINT SWELLING, PAIN, NUMBER OF INFLAMED JOINTS, DURATION OF MORNING STIFFNESS). ITS EFFECTIVENESS WAS MAINTAINED WITH LONG-TERM USE (TWO YEARS). /TOLMETIN SODIUM/
EFFICACY...IN A DAILY DOSE OF ABOUT 1.2 G WAS COMPARABLE TO...3.9 G OF ASPIRIN DAILY. /OTHER/...STUDIES IN PT WITH RHEUMATOID ARTHRITIS INDICATED...DAILY DOSE OF ABOUT 1.2 G OF TOLMETIN WAS EQUALLY EFFECTIVE TO ABOUT 150 MG INDOMETHACIN. ...SIMILAR EFFECTIVENESS /COMPARED TO/ IBUPROFEN & PHENYLBUTAZONE. /TOLMETIN SODIUM/
...SHOWN TO BE EFFECTIVE IN TREATMENT OF JUVENILE RHEUMATOID ARTHRITIS; HOWEVER, THE NUMBER OF PT STUDIED WAS SMALL & ADDNL STUDIES ARE NECESSARY TO ESTABLISH THE EFFECTIVE DOSE. /TOLMETIN SODIUM/
For more Therapeutic Uses (Complete) data for TOLMETIN (14 total), please visit the HSDB record page.

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Drug Warnings
IN CLINICAL STUDIES, PEPTIC ULCER OCCURRED IN APPROX 2% OF PT. IT IS... ADVISABLE TO USE TOLMETIN CAUTIOUSLY IN PT WITH A HISTORY OF PEPTIC ULCER. /TOLMETIN SODIUM/
TOLMETIN DECR PLATELET ADHESIVENESS & INCR BLEEDING TIME; THUS, IT SHOULD NOT BE USED IN PT WITH BLEEDING DISORDERS. /TOLMETIN SODIUM/
TOLMETIN...COMMONLY PRODUCES GASTROINTESTINAL REACTIONS (25% OF RECIPIENTS), & THEY RANGE FROM TRANSIENT MILD EFFECTS, SUCH AS NAUSEA, TO SERIOUS REACTIONS REQUIRING CESSATION OF THERAPY. ... URTICARIA, HEADACHE, WATER RETENTION, DIZZINESS, & HYPERTENSION HAVE ALSO BEEN REPORTED. /TOLMETIN SODIUM/
TOLMETIN CAUSES PSEUDOPROTEINURIA IN TESTS INVOLVING ACID PPT; THUS, OTHER METHODS FOR DETECTING PROTEINURIA SHOULD BE USED FOR PT RECEIVING THIS DRUG. /TOLMETIN SODIUM/
For more Drug Warnings (Complete) data for TOLMETIN (8 total), please visit the HSDB record page.

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Pharmacodynamics
Tolmetin is a nonsteroidal anti-inflammatory agent. Studies in animals have shown tolmetin to possess anti-inflammatory, analgesic and antipyretic activity. In the rat, tolmetin prevents the development of experimentally induced polyarthritis and also decreases established inflammation. In patients with either rheumatoid arthritis or osteaoarthritis, tolmetin is as effective as aspirin and indomethacin in controlling disease activity, but the frequency of the milder gastrointestinal adverse effects and tinnitus was less than in aspirin-treated patients, and the incidence of central nervous system adverse effects was less than in indomethacin-treated patients. In patients with juvenile rheumatoid arthritis, tolmetin is as effective as aspirin in controlling disease activity, with a similar incidence of adverse reactions. tolmetin has produced additional therapeutic benefit when added to a regimen of gold salts and, to a lesser extent, with corticosteroids. Tolmetin should not be used in conjunction with salicylates since greater benefit from the combination is not likely, but the potential for adverse reactions is increased.

C15H15NO3

257.28

257.105

26171-23-3

Tolmetin sodium dihydrate;64490-92-2;Tolmetin sodium;35711-34-3

5509

White to off-white solid powder

1.2±0.1 g/cm3

483.2±40.0 °C at 760 mmHg

156ºC

246.0±27.3 °C

0.0±1.3 mmHg at 25°C

1.582

1.55

1

3

4

19

347

0

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)

2-[1-methyl-5-(4-methylbenzoyl)pyrrol-2-yl]acetic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 100 mg/mL (388.68 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (9.72 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (9.72 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (9.72 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)