Effect of isoniazid on the metabolism of 14C-diphenylhydantoin in rats.

The effect of isoniazid (INH, 0,5, 10 or 20 mg/kg; p.o.) on the metabolic disposition of 14C-diphenylhydantoin (DPH, 50 mg/kg; i.v.) was studied in rats for 5 hours. The disappearance rate of 14C from the blood was similar up to 2 hr, whereas at 3 hr the levels of 14C were significantly higher in 10 and 20 mg/kg INH-treated rats than the controls. While the urinary excretion remained virtually unaltered, the fecal excretion of 14C was significantly reduced in the presence of INH. Increasing doses of INH caused a corresponding increase in the concentration of 14C in the blood, plasma, liver, kidney, lung, brain, skeletal muscle, fat, heart, tests and spleen. At the end of 5 hr, about 74% of the radioactivity was present as unmetabolized DPH in the plasma of control animals; this was increased significantly in a dose-related manner by INH, reaching a concentration of 93% at the highest doses of INH administered. The results suggest that the INH-induced elevation of DPH-derived 14C in plasma and its marked accumulation in other tissues is due to inhibition of both the p-hydroxylation of DPH and the glucuronidation of its metabolites.