Simultaneous kinetic modelling of plasma levels and urinary excretion of salicyluric acid, and the influence of probenecid

Summary

In a fundamental study on the effect of probenecid on the plasma kinetics and the renal handling of some organic anions known to be transported by the tubular secretion mechanism in the mammalian kidney, we measured plasma levels and urinary excretion rates of salicyluric acid in male Beagle dogs, after intravenous application of salicyluric acid, with and without co-administration of probenecid.

The animals were anaesthetized with sodium pentobarbital (30 mg/kg) and provisions were made for blood and urine sampling. In order to obtain a sufficiently high and constant urine flow, an infusion of a solution containing 5% inulin (2 ml/min) was given throughout an experiment. Inulin was added for measurement of the glomerular filtration rate.

Linear plots of the urinary excretion rate against the average plasma concentration of each urine collection period were drawn as an illustrative way to depict the relation between plasma concentration and urinary excretion rate.

In order to quantify the effect of probenecid on the plasma kinetics and the renal handling of salicyluric acid, we conceived a dynamic model, able to describe changes in plasma kinetics as well as in urinary excretion. The effect of probenecid on the pharmacokinetics of salicyluric acid can be adequately described in terms of a non-competitive inhibition of the tubular secretory mechanism for salicyluric acid. Parameters for the description of this interaction were estimated by a simulation procedure with the aid of the computer program CSMP III.