Metabolism of Aspirin after Therapeutic and Toxic Doses

Abstract

<jats:p> 1 The urinary recovery of metabolites of aspirin (ASA) was studied in 45 volunteers who took a therapeutic dose (600 mg) of ASA by mouth and in 37 patients who took ASA in overdose. </jats:p><jats:p> 2 The main metabolite recovered from the volunteers was the glycine conjugate, salicyluric acid (SUA), which accounted for 75.01 ± 1.19% of total urinary metabolites, whereas salicylic acid (SA) accounted for 8.82 ± 0.56%. Recovery of SUA was negatively correlated with that of SA (r = -0.8625, P &lt; 0.001). </jats:p><jats:p> 3 In 24 patients with admission plasma salicylate concentrations of 240-360 mg 1-1, SUA accounted for 46.66 ± 3.22% and SA for 31.88 ± 4.02%. </jats:p><jats:p> 4 In 13 patients with admission plasma salicylate concentrations of 715-870 mg 1-1, SUA accounted for 21.57 ± 3.65% and SA for 64.72 ± 4.82%. </jats:p><jats:p> 5 Reduced excretion of salicylate as SUA was also accompanied by increased elimination as gentisic acid and salicylic acid phenolic glucuronide indicating that the unsaturated processes that lead to the formation of these metabolites contribute significantly (22-23%) to the inactivation of large doses of salicylate. </jats:p><jats:p> 6 While the Michalis-Menten kinetics of ASA have been well demonstrated at lower doses, our findings illustrate the progressive saturation of SUA formation under conditions of increasing ASA load to toxic amounts and raise issues about the in-vivo glycine pool when ASA is taken in overdose. </jats:p>

Biosynthesis and metabolism of β-d-salicin: A novel molecule that exerts biological function in humans and plants

“…Salicylic acid 2 undergoes further metabolism in the liver and kidney, as part of drug clearance (Scheme 6). Cytochrome p-450 enzyme system in mitochondria is capable of catalysing salicylate into different metabolites, including 2,3,5-trihydroxy benzoic acid 32 , 2,5-dihydroxy benzoic 33 acid and catechol 34 ; the decarboxylated analogue of compound 35 [30], [31], [32]. The biotransformation is likely to involve enzymatic hydroxylation or radical oxidation.…”

A Reassessment of the Treatment of Salicylate Poisoning

“…Saturation of these pathways is the major factor delaying salicylate excretion in overdosehalf-lives of between 10 and 45h for salicylic acid have been reported (Berg 1977;Done 1960;Prescott et al 1982). Following toxic doses of aspirin, there is a significant decrease in the excretion of salicyluric acid and salicyl glucuronides, and a corresponding increase in salicylic acid (Patel 1985;Patel et al 1990a).…”

“…Salicylic acid, being an acidic drug (pKa 3.0), can depress urine pH, slowing down its own renal elimination (Patel 1985). Adjusting the urine pH from 5.4 to 7.4 theoretically increases the plasma: urine salicylic acid ratio from approximately 100 to 1.…”

“…Patients with aspirin overdose excrete a significantly reduced proportion of salicyluric acid in the urine because its formation becomes saturated (Levy et al 1969;Notarianni et al 1983;Patel et al 1990a), although the exact mechanism is not understood. Limitations both in the enzyme system (Levy 1979) and glycine availability (Patel et al 1990a) have been proposed. Recent work has indicated that diminished availability of glycine available for conjugation contributes to capacity.limited formation of salicyluric acid under conditions of aspirin poisoning (Patel et al I 990b).…”

In Vivo Effects of Naproxen, Salicylic Acid, and Valproic Acid on the Pharmacokinetics of Trichloroethylene and Metabolites in Rats

“…Acetylsalicylic acid (ASA) is a nonsteroidal anti-inflammatory drug (NSAID), with analgesic and antipyretic properties. This pharmaceutical is rapidly hydrolyzed to salicylic acid (2-hydroxybenzoic acid, SA) in the intestinal wall, liver, and red blood cells (Patel et al, 1990). Approximately 80% of the resulting SA is further biotransformed in the liver by conjugation with either glycine or glucuronic acid, or by oxidation.…”