EFFECT OF URINARY PH ON THE PHARMACOKINETICS OF SALICYLIC-ACID, WITH ITS GLYCINE AND GLUCURONIDE CONJUGATES IN HUMAN

We studied the effects of urinary pH on the kinetics of salicylic acid (SA) with its metabolites and assessed the contribution of alkaline h ydrolysis of salicylic acid acyl glucuronide to the renal clearance of salicylic acid. Hydrolysis of SAAG in alkaline urine contributes marg inally to the high renal clearance and excretion of salicylic acid, va lidating alkalinization of a patient with SA overdose. Under acidic ur ine conditions, salicylic acid (SA) had a terminal plasma tin value of 3.29 +/- 0.52 hours while under alkaline urine conditions this tin wa s 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 conditio ns (2.27 +/- 0.83 l/h; p = 0.0410). The K-m and V-max values of SA, an d its conjugates salicylic acid phenolic glucuronide (SAPG), salicylur ic acid (SU) and salicyluric acid phenolic glucuronide (SUPG) did not differ statistically under acidic and alkaline urine conditions. The p rotein 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%, w hile SAPG showed no protein binding at all. The renal excretion of sal icylic acid depends strongly on the urinary pH. The percentage of the dose excreted unchanged increased from 2.3 +/- 1.5% under acidic condi tions to 30.5 +/- 9.1% under alkaline conditions (p = 0.0006). Alkalin e 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). The renal clearance (Clr) of SA is 0. 48 +/- 0.35 ml/min in acidic urine and 11.9 +/- 6.4 ml/min in alkaline urine (p = 0.0014). The Clr of SAPG (150-200 ml/min) appeared to be u rine pH dependent (p = 0.0170). The Clr of the glycine conjugates is i ndependent of the urinary pH (SU 509 +/- 147 ml/min, and SUPG 91 +/- 1 2 ml/min). The maximal renal excretion rate of SU is 70.9 +/- 18.1 mg/ h and of SAPG 14.4 +/- 7.2 mg/h and present for 10 hours. Alkalinizati on of patients on SA overdose is an effective and valid method, and no t based on hydrolysis of salicylic acid acyl glucuronide.