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
Following oral administration of a therapeutic dose, the drug is rapidly and almost completely absorbed, with peak plasma concentrations reached within 30-60 minutes. The drug is primarily excreted in the urine, mainly as conjugates or metabolites. Its plasma half-life is approximately 1 hour. Tolmetin Sodium Gastrointestinal absorption is approximately 90% or higher…Tolmetin reaches peak concentrations within 20-60 minutes…High protein binding, reaching 90% or higher…Primarily excreted via hepatic biotransformation and renal excretion, with some metabolites excreted in feces. Tolmetin sodium is rapidly and completely absorbed by the body after oral administration, and concurrent administration of gastric acid inhibitors does not reduce plasma concentrations. Peak plasma concentrations are reached 20-60 minutes after oral administration, with a plasma half-life of 1-3 hours. After absorption, Tolmetin is extensively bound to plasma proteins (99%). Almost all of the drug is recovered from urine after 24 hours; some drugs remain unchanged (17%), but most undergo conjugation (10%) or other metabolisms. The main metabolic transformation is decarboxylation. Tolmetin sodium is rapidly and completely absorbed (peak time 20–60 minutes) and rapidly eliminated from plasma with a biphasic decay curve, with an elimination half-life of approximately 2.1 hours. Metabolites/Metabolites: Almost all administered doses are recovered from urine within 24 hours as inactive oxidized metabolites or Tolmetin conjugates. Metabolites detected in urine after Tolmetin administration include 1-methyl-5-(4-carboxybenzoyl)-1H-pyrrole-2-acetic acid and Tolmetin glucuronide sodium. Known human metabolites of Tolmetin include Tolmetin glucuronide.

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Biological half-life
Elimination from plasma is biphasic, consisting of a rapid elimination phase with a half-life of 1 to 2 hours, followed by a slower elimination phase with a half-life of approximately 5 hours.

Hepatotoxicity
Up to 5% of patients taking tometetin long-term may experience at least transient increases in serum transaminases. These symptoms may resolve spontaneously with continued use. Significant transaminase elevations (more than 3-fold increase) are seen on a probability score of D (probable, but rare, and a clinically significant cause of liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation Due to the low concentration and short half-life of tometetin in breast milk, adverse effects on breastfed infants are unlikely. However, since there is currently no published experience regarding breastfeeding during tometetin treatment, alternative medications may be preferred, especially for newborns or premature infants. ◉ Effects on Breastfed Infants No published information found as of the revision date. ◉ Effects on Lactation and Breast Milk No published information found as of the revision date.

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Interactions
Patients receiving corticosteroids or gold preparations showed more significant symptom relief when tometetin was added to their treatment regimen, and there is evidence that tometetin has a steroid replacement effect. /Tometetin Sodium/
Tometetin combined with acetaminophen improves symptoms more than tometetin alone, but further research is needed to confirm this effect. /Tometetin Sodium/
Co-administration with aspirin reduces tometetin plasma concentrations by approximately 20%, but this interaction may not be clinically significant. /Tometetin Sodium/
In dogs, the prostaglandin synthase inhibitor indomethacin and tometetin block furosemide-induced increases in renin secretion, regardless of whether furosemide is administered intravenously or via the renal artery.
Although it binds extensively to albumin… there was no change in prothrombin time when warfarin and tometetin were administered concurrently.

[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, a compound in which 1-methylpyrrole-2-ylacetic acid is substituted at the 5-position of the pyrrole ring with a 4-methylbenzoyl group. It is used as a non-selective nonsteroidal anti-inflammatory drug (NSAID) in the form of its sodium dihydrate. It is both an NSAID and a prostaglandin intraperoxidase (EC 1.14.99.1) inhibitor. It belongs to the pyrrole class of compounds, monocarboxylic acids, and aromatic ketones. It is the conjugate acid of Tolmetin (1-). Tolmetin is a nonsteroidal anti-inflammatory drug (NSAID) with a mechanism of action similar to indomethacin. Tolmetin is a nonsteroidal anti-inflammatory drug. The mechanism of action of Tolmetin is as a cyclooxygenase inhibitor. Tolmetin is a prescription NSAID used to treat chronic arthritis. Elevated serum transaminases during Tolmetin treatment are rare but have been associated with rare, clinically significant cases of drug-induced liver injury.
Tolmetin is an arylalkyl acid nonsteroidal anti-inflammatory drug (NSAID) with analgesic, anti-inflammatory, and antipyretic effects. Although the exact mechanism of action of Tolmetin is not fully elucidated, the drug appears to inhibit prostaglandin synthase. This prevents the formation of prostaglandin precursors, including the synthesis of inflammatory prostaglandin E2 (PGE2) from its precursor prostaglandin H2 (PGH2). This can prevent prostaglandin-mediated effects, including pain, inflammation, and fever.
A nonsteroidal anti-inflammatory drug (NSAID) with a mechanism of action similar to indomethacin.
See also: Tolmetin sodium (in salt form); amotoprine guaiacol glycerol ether (its active ingredient).
Indications
For the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis, including the treatment of acute flare-ups and long-term management. Also used to treat juvenile rheumatoid arthritis.
FDA Label

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Mechanism of Action
The mechanism of action of tometetin is not fully understood. However, studies in experimental animals and humans have shown that the anti-inflammatory effect of tometetin is not due to stimulation of the pituitary-adrenal axis. Tometetin inhibits prostaglandin synthase in vitro and reduces the level of prostaglandin E in human plasma. The reduction in prostaglandin synthesis may be the cause of its anti-inflammatory effect. Tometetin does not appear to alter the course of the primary disease in humans.
Although its chemical structure differs from aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), its pharmacological properties are similar. /Tometetin Sodium/
...In vitro, it inhibits prostaglandin synthase. It has also been shown to reduce the level of prostaglandin E in human plasma. However, the relationship between these effects and clinical efficacy is unclear. /Tometetin Sodium/

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Therapeutic Use
Nonsteroidal anti-inflammatory drug; cyclooxygenase inhibitor
In several controlled studies in patients with rheumatoid arthritis, tometetin reduced the severity of symptoms (joint swelling, pain, number of inflamed joints, duration of morning stiffness). Its efficacy can be maintained with long-term use (two years). /Tolmetin Sodium/
Approximately 1.2 grams daily is equivalent to 3.9 grams daily aspirin. Other studies have shown that in patients with rheumatoid arthritis, approximately 1.2 grams of Tolmetin daily is equivalent to approximately 150 mg of indomethacin. Its efficacy is similar to ibuprofen and phenylbutazone. Tolmetin sodium has been shown to be effective in treating juvenile rheumatoid arthritis; however, the number of patients studied is small, and more studies are needed to determine the effective dose. /Tolmetin Sodium/
For more complete data on the therapeutic uses of Tolmetin (14 types), please visit the HSDB record page.

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Drug Warnings
Approximately 2% of patients developed peptic ulcers in clinical studies. Caution is advised when using Tolmetin in patients with a history of peptic ulcer disease. /Tolmetin Sodium/
Tolmetin can reduce platelet adhesion and prolong bleeding time; therefore, it should not be used in patients with bleeding disorders. Tometin Sodium
Tometin…commonly causes gastrointestinal reactions (25% of patients), ranging in severity from transient mild reactions (such as nausea) to severe reactions requiring discontinuation of treatment. …Hives, headache, edema, dizziness, and hypertension have also been reported. Tometin Sodium
Tometin can cause false proteinuria in acid precipitation tests; therefore, patients taking this medication should have proteinuria detected using alternative methods. /Tometin Sodium/
For more complete data on drug warnings for tometin (8 of 8), please visit the HSDB record page.

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Pharmacodynamics
Tometin is a nonsteroidal anti-inflammatory drug (NSAID). Animal studies have shown that tometin has anti-inflammatory, analgesic, and antipyretic effects. In rats, tometin prevented the development of experimentally induced polyarthritis and reduced existing inflammation. In patients with rheumatoid arthritis or osteoarthritis, tolmetine is as effective as aspirin and indomethacin in controlling disease activity, but has a lower incidence of mild gastrointestinal side effects and tinnitus compared to aspirin-treated patients, and a lower incidence of central nervous system side effects compared to indomethacin-treated patients. In patients with juvenile rheumatoid arthritis, tolmetine is comparable to aspirin in controlling disease activity, and the incidence of adverse reactions is also similar. Combining tolmetine with gold salts can produce additional therapeutic benefits, while the effect is slightly weaker when combined with corticosteroids. Tolmetine should not be used in combination with salicylates, as this combination is unlikely to provide greater benefits and may instead increase the risk of adverse reactions.

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.)