The tissue distribution and pharmacokinetics of saccharin in the rat

The concentration of saccharin in the plasma of rats fed a 5% saccharin diet showed marked diurnal variations. In male rats given 1–10% saccharin diets for 22 days the concentrations in the kidneys and bladder were higher than the plasma, while other tissues contained less than the plasma. The concentrations of saccharin in the plasma and tissues of female rats given 5% saccharin diet were higher than males treated similarly. The decrease in saccharin concentration in the bladder wall on removal of 5% saccharin diet, and after iv administration of [ 3H]saccharin to normal rats, reflected the decrease in urine and plasma levels. The concentrations of saccharin in the plasma and tissues of male rats given 7.5 and 10% saccharin diets were higher than predicted by linear extrapolation from lower dietary levels. The plasma clearance of [ 3H]saccharin given iv was dose dependent in anesthetized rats with high doses showing a 60% decrease in clearance. A similar reduction (70%) in clearance was achieved by prior treatment of the rats with probenecid. Decreased plasma clearance was also demonstrated under steady-state infusion conditions, at plasma concentrations greater than 200–300 μg ml −1. The concentrations of saccharin in the plasma of rats given 7.5 and 10% saccharin diets were sufficient to saturate plasma clearance and thus cause the elevated concentrations of saccharin observed in the tissues of such animals.