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  • Title: Isoniazid-induced inhibition in the biotransformation of [14C] diphenylhydantoin in rat.
    Author: Buttar HS.
    Journal: Res Commun Chem Pathol Pharmacol; 1977 Sep; 18(1):35-57. PubMed ID: 905633.
    Abstract:
    The effect of isoniazid (0,10,20 and 40 mg/kg; i.v.) on the biliary and urinary excretion of [14C] diphenylhydantoin (DPH, 50 mg/kg; i.v.) was investigated in biliary-fistulated rats during the first 5 hours. Isoniazid cause a dose-dependent reduction in the total biliary excretion of 14 C without affecting its output in urine. After 5 h, maximal levels of radioactivity were recorded in the liver, followed by heart and brain. The glucuronides of DPH metabolites accounted for most of the 14C in 5 h pooled bile, less than 1% of the injected dose was excreted as unmetabolized DPH. Isoniazid administration caused the following significant dose-related changes in biliary excretion: (a) increased excretion of the unconjugated principal DPH metabolite, 5-(p-hydroxyphenyl)-5-phenylhydantion (HPPH); (b) decreased excretion of HPPH-glucuronide; and (c) increased excretion of the glucuronide conjugates of the polar metabolites of DPH. The results suggest that the isoniazid-induced elevation of DPH-derived 14C in blood and its marked accumulation in brain, heart and liver is due to inhibition of p-hydroxylation of DPH and the glucuronidation of HPPH.
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