Absorption, Distribution and Excretion
Salsalate is insoluble in acid gastric fluids (< 0.1 mg/ml at pH 1.0), but readily soluble in the small intestine where it is partially hydrolyzed to two molecules of salicylic acid. A significant portion of the parent compound is absorbed unchanged. The amount of salicylic acid available from salsalate is about 15% less than from aspirin, when the two drugs are administered on a salicylic acid molar equivalent basis (3.6 g salsalate/5 g aspirin). Food slows the absorption of all salicylates including salsalate.

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Metabolism / Metabolites
Salsalate is readily soluble in the small intestine where it is partially hydrolyzed to two molecules of salicylic acid. A significant portion of the parent compound is absorbed unchanged and undergoes rapid esterase hydrolysis in the body.

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Biological Half-Life
The parent compound has an elimination half-life of about 1 hour. Salicylic acid (the active metabolite) biotransformation is saturated at anti-inflammatory doses of salsalate. Such capacity limited biotransformation results in an increase in the half-life of salicylic acid from 3.5 to 16 or more hours.

Hepatotoxicity
Prospective studies show that a proportion of patients taking salsalate experience at least transient serum aminotransferase elevations particularly when it is given in higher doses. These abnormalities may resolve even with drug continuation or after dose reduction. Marked aminotransferase elevations (>10 fold elevated) occur rarely except with use of higher doses (4 g daily or more) in a manner similar to aspirin. Clinically apparent liver injury with jaundice from salsalate has not been reported and must be very rare. Salsalate is probably capable of inducing Reye syndrome in a susceptible child or adolescent and, like aspirin, should be avoided in those age groups.
Likelihood score: A[HD] (well established cause of liver injury if given in high doses).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Salsalate has not been studied during breastfeeding, but salsalate results in salicylic acid in the blood. Salicylic acid and aspirin have been studied during breastfeeding. The excretion of salicylate into breastmilk increases disproportionately as the maternal dosage increases. Long-term, high-dose maternal aspirin ingestion probably caused metabolic acidosis in one breastfed infant. Reye's syndrome is associated with aspirin administration to infants with viral infections, but the risk of Reye's syndrome from salicylate in breastmilk is unknown. An alternate drug is preferred over salsalate.
◉ Effects in Breastfed Infants
A 16-day-old breastfed infant developed metabolic acidosis with a salicylate serum level of 240 mg/L and salicylate metabolites in the urine. The mother was taking 3.9 grams daily of aspirin for arthritis, and salicylate in breastmilk probably caused the infant's illness, but the possibility of direct administration to the infant could not be ruled out.
Thrombocytopenia, fever, anorexia and petechiae occurred in a 5-month-old breastfed infant 5 days after her mother started taking aspirin for fever. One week after recovery, the infant was given a single dose of aspirin 125 mg and the platelet count dropped once again. The original symptoms were probably caused by salicylate in breastmilk.
Hemolysis after aspirin and phenacetin taken by the mother of a 23-day-old, glucose-6-phosphate dehydrogenase (G6PD) deficient infant was possibly due to aspirin in breastmilk.
In a telephone follow-up study, mothers reported no side effects among 15 infants exposed to aspirin (dose and infant age unspecified) in breastmilk.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Salicylate: 90-95% bound at plasma salicylate concentrations <100 mcg/mL; 70-85% bound at concentrations of 100-400 mcg/mL; 25-60% bound at concentrations >400 mcg/mL.

[1]. Effects of salsalate therapy on recovery from vascular injury in female Zucker fatty rats. Diabetes. 2010;59(12):3240-3246.

[2]. Gastroduodenal mucosal damage with salsalate versus aspirin: results of experimental models and endoscopic studies in humans. Semin Arthritis Rheum. 1990;20(2):121-127.

[3]. Salicylate administration suppresses the inflammatory response to nutrients and improves ovarian function in polycystic ovary syndrome. Am J Physiol Endocrinol Metab. 2020;319(4):E744-E752.

Salsalate is a dimeric benzoate ester obtained by intermolecular condensation between the carboxy of one molecule of salicylic acid with the phenol group of a second. It is a prodrug for salycylic acid that is used for treatment of rheumatoid arthritis and osteoarthritis and also shows activity against type II diabetes. It has a role as a non-steroidal anti-inflammatory drug, a non-narcotic analgesic, an antirheumatic drug, a hypoglycemic agent, an antineoplastic agent, an EC 3.5.2.6 (beta-lactamase) inhibitor and a prodrug. It is a benzoate ester, a member of benzoic acids, a member of phenols and a member of salicylates. It is functionally related to a salicylic acid.
Salsalate is a nonsteroidal anti-inflammatory agent for oral administration. Salsalate's mode of action as an anti-inflammatory and antirheumatic agent may be due to inhibition of synthesis and release of prostaglandins. The usefulness of salicylic acid, the active in vivo product of salsalate, in the treatment of arthritic disorders has been established. In contrast to aspirin, salsalate causes no greater fecal gastrointestinal blood loss than placebo. Salsalate is readily soluble in the small intestine where it is partially hydrolyzed to two molecules of salicylic acid. A significant portion of the parent compound is absorbed unchanged and undergoes rapid esterase hydrolysis in the body. The parent compound has an elimination half-life of about 1 hour. Salicylic acid (the active metabolite) biotransformation is saturated at anti-inflammatory doses of salsalate. Such capacity limited biotransformation results in an increase in the half-life of salicylic acid from 3.5 to 16 or more hours.
Salsalate is a nonacetylated dimer of salicylic acid that is used in the treatment of chronic arthritis as an analgesic and antipyretic. Salsalate can cause moderate serum aminotransferase elevations when given in high doses in a manner similar to aspirin.
Salsalate is an orally available salicylate and non-steroidal anti-inflammatory drug (NSAID), with anti-inflammatory, analgesic and antipyretic activities. As a prodrug, salsalate is hydrolyzed to salicylic acid which inhibits the expression of cyclooxygenase (COX) enzymes. This prevents the conversion of arachidonic acid into prostaglandin precursors and leads to decreased formation of prostaglandins that are involved in pain, fever and inflammation. In addition, salsalate appears to inhibit nuclear factor-kappa B (NF-kB), thereby preventing activation of the NF-kB-mediated pathway and the expression of genes involved in inflammation.
See also: Salsalate sodium (is active moiety of).

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Drug Indication
For relief of the signs and symptoms of rheumatoid arthritis, osteoarthritis and related rheumatic disorders.

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Mechanism of Action
The mode of anti-inflammatory action of salsalate and other nonsteroidal anti-inflammatory drugs is not fully defined, but appears to be primarily associated with inhibition of prostaglandin synthesis. This inhibition of prostaglandin synthesis is done through the inactivation of cyclooxygenase-1 (COX-1) and COX-2, which are reponsible for catalyzing the formation of prostaglandins in the arachidonic acid pathway. Although salicylic acid (the primary metabolite of salsalate) is a weak inhibitor of prostaglandin synthesis in vitro, salsalate appears to selectively inhibit prostaglandin synthesis in vivo, providing anti-inflammatory activity equivalent to aspirin and indomethacin. Unlike aspirin, salsalate does not inhibit platelet aggregation.

C14H10O5

28.23

258.052

552-94-3

Salsalate (Standard);552-94-3

5161

White to off-white solid powder

1.4±0.1 g/cm3

482.9±25.0 °C at 760 mmHg

139-151 °C

188.0±16.7 °C

0.0±1.3 mmHg at 25°C

1.646

3.05

2

5

4

19

341

0

O=C(OC1=CC=CC=C1C(O)=O)C2=CC=CC=C2O

WVYADZUPLLSGPU-UHFFFAOYSA-N

InChI=1S/C14H10O5/c15-11-7-3-1-5-9(11)14(18)19-12-8-4-2-6-10(12)13(16)17/h1-8,15H,(H,16,17)

2-(2-hydroxybenzoyl)oxybenzoic acid

Salsalate Salicylsalicylic acid Sasapyrine Disalicylic acid disalicylic acid Disalcid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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 (~387.25 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (9.68 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 (9.68 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 (9.68 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.)