Capacity-Limited Salicylurate Formation During Prolonged Administration of Aspirin to Healthy Human Subjects

1 The pharmacokinetics of salicyclic acid (SA) and its major metabolite salicyluric acid (SU) were studied in nine patients with rheumatoid arthritis following a 900 mg oral dose of acetylsalicylic acid and during 6 weeks of chronic administration of enteric coated aspirin (3,900 mg day). Response to therapy was also monitored. 2 The various pharmacokinetic parameters determined in the study were similar to those observed in other single dose salicylate studies amongst healthy volunteers but were not predictive of salicylate concentration in the chronic dose study. 3 Plasma concentrations of SA (total and unbound) were found to decline significantly over the 6 weeks and plasma SU concentrations increased. 4 During the chronic dosing study, there was a significant increase in the Vmax (total and unbound) for the formation of SU, whilst the Km and SU clearance remained constant. Also, the elimination rate constant (k) for salicylate was not significantly affected. 5 Therapeutic response to salicylate therapy was not significantly affected by the decline in SA concentrations.

Section: Discussioncontrasting

confidence: 80%

Salicylate pharmacokinetics in patients with rheumatoid arthritis.

Roberts

Friesen

et al. 1989

“…Figure 3 shows the fraction of total urinary salicylate excreted as free salicylic acid and individual (1975) and in the present study, it may have been observed in other studies but not recognized. Levy, Vogel & Amsel (1969), for instance, reported that for certain subjects receiving 2.4 g/day of aspirin for 8 days then 7.2 g daily for the next 8 days, plasma salicylate levels had declined by day 15. They attributed this effect to poor subject compliance.…”

Section: Resultsmentioning

confidence: 99%

Metabolism of salicylate during chronic aspirin therapy.

Rumble¹,

Brooks²,

Roberts³

1980

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.

“…The formation pathways of salicyluric acid and salicyl phenolic glucuronide are saturable and follow Michaelis-Menten type kinetics (Levy et al, 1969a(Levy et al, , 1972 The model dependent and independent pharmacokinetic parameters were tested statistically using a 2 x 2 factorial analysis of variance which considered the factor age (A) with 1 degree of freedom (df), the factor sex (S) (1 df), and the interaction of both (A x S) (1 df) in order to determine the influence of these factors. Comparison of individual patient group data was performed by Student's t-test.…”

Section: Introductionmentioning

confidence: 99%

The effects of age and sex on the disposition of acetylsalicylic acid and its metabolites.

Ho¹,

Triggs²,

Bourne³

et al. 1985

The disposition of a low dose (600 mg) of acetylsalicylic acid (ASA) and its metabolites (salicylate, salicyluric acid and salicyl glucuronides) was studied in 25 male and female patients of different ages. Plasma levels of ASA and salicylate were found to be significantly higher in the females (young and elderly), whereas plasma levels of salicyluric acid were found to be significantly higher in the elderly (male and female) groups. The higher plasma levels of ASA and salicylate in the females appear to be due to an intrinsically lower metabolic activity in that sex, while the lower clearance of salicyluric acid leads to the accumulation of that compound in the aged. No age and sex effects were found to influence the volumes of distribution of ASA, salicylate and salicyluric acid.