We studied the effects of urinary pH on the kinetics of salicylic acid (SA) with its metabolites and assessed the contribution of alkaline hydrolysis of salicylic acid acyl glucuronide to the renal clearance of salicylic acid. Hydrolysis of SAAG in alkaline urine contributes marginally to the high renal clearance and excretion of salicylic acid, validating alkalinization of a patient with SA overdose. Under acidic urine conditions, salicylic acid (SA) had a terminal plasma t1/2 value of 3.29 +/- 0.52 hours while under alkaline urine conditions this t1/2 was significantly reduced to 2.50 +/- 0.41 hours (p = 0.0156). The total oral body clearance of salicylic acid under acidic conditions (1.38 +/- 0.43 l/h) is significantly lower than under alkaline urine conditions (2.27 +/- 0.83 l/h; p = 0.0410). The Km and Vmax values of SA, and its conjugates salicylic acid phenolic glucuronide (SAPG), salicyluric acid (SU) and salicyluric acid phenolic glucuronide (SUPG) did not differ statistically under acidic and alkaline urine conditions. The protein binding of SA was 93.8 +/- 1.0% and that of SU was 89.7 +/- 2.2% in vivo and in vitro. SUPG had a protein binding of 84.8 +/- 1.8%, while SAPG showed no protein binding at all. The renal excretion of salicylic acid depends strongly on the urinary pH. The percentage of the dose excreted unchanged increased from 2.3 +/- 1.5% under acidic conditions to 30.5 +/- 9.1% under alkaline conditions (p = 0.0006). Alkaline urine lowered by 50% the percentage of the dose excreted as SU (p = 0.0028), SAAG (p = 0.0013), and SUPG (p = 0.0296), while SAPG is only marginally lowered (p = 0.0589).(ABSTRACT TRUNCATED AT 250 WORDS)