Pharmacokinetics, metabolism and disposition of salicylate in protein-deficient rats

Abstract

The influence of dietary protein deficiency on the pharmacokinetics, metabolism, and disposition of sodium salicylate was investigated in Sprague-Dawley male rats. Animals were fed for 3 weeks a 21% (control) or a 5% (deficient) protein diet ad lib.; an additional group of rats (pair-fed controls) was fed for 3 weeks the control 21% protein diet in a restricted quantity (10 g/day/rat), which was approximately equal to the quantity (9.8 g/day) consumed by rats receiving the 5% protein diet ad lib. Sodium salicylate (in salicyclic acid equivalents) and its metabolites were assayed by HPLC. In both control and protein-deficient rats, sodium salicylate kinetics were dose-dependent and the decline in its plasma concentration proceeded according to a first-order process; no differences in the two groups of animals were found with respect to the following features of the biological fate of salicylate: plasma half-life and clearance at a 2-mg/kg (iv) dose level, volume of distribution at all dose levels (2, 10, and 100 mg/kg, iv), relative bioavailability by oral route, tissue distribution, and the rate of urinary excretion of salicyl glucuronides at 10-mg/kg dose level. However, at high dose levels (10 and 100 mg/kg, iv), the plasma half-life of salicylate was shorter and its clearance greater in protein-deficient than in control rats. The following additional changes were caused by dietary protein deficiency: a decrease in salicylate binding to serum protein, an increase in the metabolic transformation of salicylic acid to its glycine conjugate, salicyluric acid, by kidney mitochondrial preparations, an increase in the urinary excretion of salicyluric acid and salicylic acid, and a decrease in the elimination half-life of salicylic acid; the excretion of salicyluric acid proceeded according to a first-order process in protein-deficient rats but according to an apparent zero-order process in the controls. The changes in the plasma half-life and clearance of salicylate in pair-fed controls were not significant; it appears that a deficiency of both proteins and calories (protein-deficient rats) exerts greater influence on the biological fate of salicylate than does a deficiency mainly of calories (pair-fed controls). It is suggested that the decrease in the plasma half-life of salicylate in protein-deficient rats is the result of an increase in its clearance, which in turn is caused by a decrease in protein-salicylate binding and an increase in the metabolism of salicylic acid to salicyluric acid. These results point to the desirability of a systematic study of the biological fate of salicylate during clinical malnutrition, which is common in developing countries.