Changes in salicylate serum concentration and metabolism during chronic dosing in normal volunteers

Steady-state serum salicylic acid (SA) concentrations and the formation rates of salicyluric acid (SU), salicylphenolic glucuronide (SPG), salicylacyl glucuronide (SAG), and gentistic acid (GA), and the excretion rate of unchanged SA were determined in three normal subjects following the administration of a single oral dose of acetylsalicylic acid (ASA) 37 mg kg-1 and during multiple dosing with ASA 56 mg kg-1 day-1. Steady-state SA concentrations fell 23 per cent during the 4-week study period (mean +/- SD: 239 +/- 35 to 183 +/- 23 micrograms ml-1; p less than 0.05). Absorption of drug did not decrease during this time. Significant increases in the Vmax for SU and SPG formation occurred between baseline and during multiple dosing. Mean Vmax SU increased from 0.93 to 1.68 mg kg-1 h-1 (p less than 0.05) and mean Vmax SPG increased from 0.09 to 0.19 mg kg-1 h-1 (p less than 0.05). First-order rate constants for the formation of SAG and GA and for the excretion of unchanged SA did not change significantly between baseline and multiple dosing. The mechanism for the decline in CpssSA with time during high-dose SA therapy is most likely due to the induction of the formation rates of the major metabolites of SA, namely SU and SPG.