Isoniazid-induced inhibition in the biotransformation of [14C] diphenylhydantoin in rat.
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.
D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism; D001711:Biotransformation / Q000187:drug effects; D001826:Body Fluids / Q000378:metabolism; D002854:Chromatography, Paper; D003864:Depression, Chemical; D004347:Drug Interactions; D007538:Isoniazid / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010672:Phenytoin / Q000097:blood / Q000378:metabolism* / Q000652:urine; D051381:Rats; D013997:Time Factors
D010672:Phenytoin; D007538:Isoniazid