Metabolism of salicylate during chronic aspirin therapy.

Abstract

1. The effects of chronic administration of aspirin in therapeutic doses (3.9 g/day) on plasma and salivary salicylate levels were studied in eight subjects. 2. The urinary excretion profile for free salicylic acid and metabolites of salicylate were examined. 3. Plasma and salivary salicylate levels declined significantly after peak levels were achieved between days 3 and 10. 4. The decline in plasma and salivary salicylate levels may be due to an induction of a metabolic pathway such as salicylurate formation (Furst, Gupta & Paulus, 1977). Only the mean fraction of salicylate excreted as salicylurate appears to increase with time during the present study, although the change was not significant statistically. 5. The decline in plasma and salivary salicylate levels during chronic therapy may lead to an apparent ‘tolerance’ of some rheumatoid patients to aspirin.

Salicylate pharmacokinetics in patients with rheumatoid arthritis.

“…In the absence of other explanations, the decrease in plasma salicylate concentrations has been attributed to induction of the formation of salicyluric acid. Furst et al (1977) observed a significant increase in the Vmax for salicylurate formation from 0.92 mg kg-1 h-1 to 1.36 mg kg-' h-1, after only 3 days of oral aspirin therapy in 26 healthy subjects, while Rumble et al (1980) observed a nonsignificant increase in the urinary output of salicylurate during chronic dosing. Day et al (1983Day et al ( , 1988 suggested that the induction process was time-limited, with no further increase in Vmax after 2 weeks.…”

“…Box 252C, Hobart, Tasmania 7001, Australia state drug concentrations, studies in healthy subjects have reported a significant decline in steady-state plasma salicylate concentration during chronic administration of therapeutic doses of aspirin (Miiller et al, 1975;Olsson 1983;Rumble et al, 1980). Many questions about the actual nature of this observed decline and associated efficacy also remain unanswered.…”

“…Many questions about the actual nature of this observed decline and associated efficacy also remain unanswered. Rumble et al (1980) reported that the decrease could not be attributed to factors associated with the absorption of the drug or changes in renal function. In the absence of other explanations, the decrease in plasma salicylate concentrations has been attributed to induction of the formation of salicyluric acid.…”

“…Although reference has been made to the development of tolerance to aspirin during chronic therapy in patients with RA (Rumble et al, 1980), no controlled study of the phenomenon has been performed. Whether authors (e.g.…”

“…Nevertheless it is widely reported in the literature that a plasma salicylate concentration greater than 150 ,ug ml-' is required for anti-inflammatory effects. All studies observing a decrease in steady-state salicylate concentration during chronic aspirin administration to healthy volunteers (Muller et al, 1975;Olsson, 1983;Rumble et al, 1980), reported subjects in whom the plasma drug concentrations had declined to below 150 ,ug ml-. No similar studies have been conducted in patients with rheumatoid arthritis.…”