Availability of salicylate from salsalate and aspirin

Dromgoole, Sydney H.; Cassell, Sidney; Fürst, Daniel E.; Paulus, Harold E.

doi:10.1038/clpt.1983.211

Cited by 20 publications

(11 citation statements)

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“…In this study FSA after aspirin ingestion was 0.74 on average, which is lower than those reported in adult subjects [2,7], Mean absorption time as an index of an absorption rate was 0.8 h (table 2, fig 1), which is also apparently longer than the absorption halflife of aspirin in aqueous solution (4.5-16 min) [2]. Poor absorption of aspirin re lated to acute-phase Kawasaki disease [1,6] is not likely to play a role in this study, because the patients had recovered from the acute phase for more than 6 months.…”

Section: Discussioncontrasting

confidence: 48%

“…Although the poor absorption re portedly returns to near normal in the con valescence, the average bioavailability of 0.75 in the early convalescent phase is still may need to be adjusted to as low as 50% of the optimal oral dose during the febrile perilower than usually expected in adults [2,7], This prompted us to assess the bioavailabil ity of aspirin in pediatric patients with prior Kawasaki disease.…”

Section: Discussionmentioning

confidence: 99%

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Disposition of Single-Dose Intravenous and Oral Aspirin in Children

Itô¹,

Oka²,

Tsuchida³

et al. 1991

Dev Pharmacol Ther

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We described the pharmacokinetics of acetylsalicylic acid and salicylic acid in 5 children with prior Kawasaki disease receiving buffered aspirin tablets or intravenous aspirin DL-lysine. Oral aspirin is characterized by its longer mean residence time in the body (MRT), an indicator for duration of exposure, than intravenous aspirin (1.18 vs. 0.37 h). The apparent elimination half-life (t(1/2)) of acetylsalicylic acid was also longer after oral than after intravenous administration of aspirin (40 vs. 17 min). The mean absorption time was calculated to be as long as 0.8 h. In contrast, the two modes of administration gave virtually identical results regarding MRT of salicylic acid proper and its t(1/2). After oral administration of aspirin, 51% of the dose is absorbed intact as acetylsalicylic acid while 23% is converted to salicylic acid presystemically, indicating that 74% of aspirin is actually absorbed. Our data suggest that an equivalent intravenous aspirin dose to achieve the same salicylic acid concentration is about 70% of the oral dose. However, the area under the curve of acetylsalicylic acid itself, a more potent cyclooxygenase inhibitor than salicylic acid, would be about 1.5 times higher than that following oral administration. The clinical consequences of this exposure difference remain uncertain.

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Section: Discussioncontrasting

confidence: 48%

Section: Discussionmentioning

confidence: 99%

Disposition of Single-Dose Intravenous and Oral Aspirin in Children

Itô¹,

Oka²,

Tsuchida³

et al. 1991

Dev Pharmacol Ther

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“…The amount of salicyl glucuronides in urine was determined by difference after acid hydrolysis of all conjugates (Dromgoole et al, 1983) and estimation of total salicylic acid by the h.p.l.c. method described above.…”

Section: Analyticalmentioning

confidence: 99%

Influence of gender and oral contraceptive steroids on the metabolism of salicylic acid and acetylsalicylic acid.

Miners¹,

Grgurinovich²,

Whitehead

et al. 1986

Brit J Clinical Pharma

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Salicylic acid and acetylsalicylic acid (aspirin) disposition after an oral dose of aspirin, 900 mg (equivalent to 689.7 mg of salicylic acid) was studied in eight males, eight females and eight females receiving oral contraceptive steroids (OCS). Salicylic acid clearance was 61% higher in males compared to the control female group, an effect due largely to enhanced activity of the glycine conjugation pathway (salicyluric acid formation) in males. Salicylic acid clearance was 41% higher in OCS‐users compared to the control female group due to increases in both the glycine and glucuronic acid conjugation pathways in the pill users. There was no difference in any salicylic acid disposition parameter between males and OCS‐users. Area under the plasma concentration‐time curve (AUC) and elimination half‐life of aspirin was significantly greater and aspirin plasma hydrolysis rate was significantly lower in both female groups compared to males. There was no difference between OCS‐users and the control female group in any of these parameters. Aspirin AUC and elimination half‐life were significantly correlated with aspirin plasma hydrolysis rate. These data confirm the importance of hormonal factors in the regulation of drug conjugation reactions in humans and suggest that sex‐related differences in salicylic acid and aspirin disposition may be of clinical importance.

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“…Salsalate is a prodrug of salicylate and is hydrolyzed in the small intestine to produce two molecules of salicylate (3,4). The circulating concentration of salicylate in humans administered salsalate in T2D clinical trials is ~1 mmol/L (5-8).…”

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confidence: 99%

Salsalate (Salicylate) Uncouples Mitochondria, Improves Glucose Homeostasis, and Reduces Liver Lipids Independent of AMPK-β1

et al. 2016

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Salsalate is a prodrug of salicylate that lowers blood glucose in patients with type 2 diabetes (T2D) and reduces nonalcoholic fatty liver disease (NAFLD) in animal models; however, the mechanism mediating these effects is unclear. Salicylate directly activates AMPK via the β1 subunit, but whether salsalate requires AMPK-β1 to improve T2D and NAFLD has not been examined. Therefore, wild-type (WT) and AMPK-β1-knockout (AMPK-β1KO) mice were treated with a salsalate dose resulting in clinically relevant serum salicylate concentrations (~1 mmol/L). Salsalate treatment increased VO 2 , lowered fasting glucose, improved glucose tolerance, and led to an ~55% reduction in liver lipid content. These effects were observed in both WT and AMPK-β1KO mice. To explain these AMPK-independent effects, we found that salicylate increases oligomycin-insensitive respiration (state 4o) and directly increases mitochondrial proton Corresponding author: Gregory R. Steinberg, gsteinberg@mcmaster.ca. Duality of Interest. No potential conflicts of interest relevant to this article were reported.Author Contributions. B.K.S. and G.R.S. designed research studies, analyzed data, and wrote the manuscript. B.K.S., R.J.F., E.M.D., A.E.G., M.C.H., V.P.H., E.A.D., K.M., J.D.C., E.P.M., and C.G.R.P. conducted experiments and analyzed data. B.K.S., R.J.F., E.M.D., A.E.G., V.P.H., E.A.D., K.M., J.D.C., E.P.M., B.E.K., M.A.T., and G.R.S. edited the manuscript. G.R.S. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db16-0564/-/DC1. Diabetes. Author manuscript; available in PMC 2017 January 12.Published in final edited form as:Diabetes. 2016 November ; 65(11): 3352-3361. doi:10.2337/db16-0564. CIHR Author Manuscript CIHR Author Manuscript CIHR Author Manuscriptconductance at clinical concentrations. This uncoupling effect is tightly correlated with the suppression of de novo lipogenesis. Salicylate is also able to stimulate brown adipose tissue respiration independent of uncoupling protein 1. These data indicate that the primary mechanism by which salsalate improves glucose homeostasis and NAFLD is via salicylate-driven mitochondrial uncoupling.Nonalcoholic fatty liver disease (NAFLD) is considered an important contributing factor to the development of insulin resistance and type 2 diabetes (T2D) (1). Despite the rising prevalence of NAFLD and importance for the development of T2D, there are currently no pharmacological approaches for the treatment of this disease (2).Salsalate is a prodrug of salicylate and is hydrolyzed in the small intestine to produce two molecules of salicylate (3,4). The circulating concentration of salicylate in humans administered salsalate in T2D clinical trials is ~1 mmol/L (5-8). Salsalate has also been shown to improve symptoms of NAFLD (9) and nonalcoholic steatohepatitis in...

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Availability of salicylate from salsalate and aspirin

Cited by 20 publications

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Disposition of Single-Dose Intravenous and Oral Aspirin in Children

Disposition of Single-Dose Intravenous and Oral Aspirin in Children

Influence of gender and oral contraceptive steroids on the metabolism of salicylic acid and acetylsalicylic acid.

Salsalate (Salicylate) Uncouples Mitochondria, Improves Glucose Homeostasis, and Reduces Liver Lipids Independent of AMPK-β1

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