Effect of diphenylhydantoin and its main hydroxylated metabolite on the pharmacokinetics and the urinary and biliary excretion of phenobarbital and its p-hydroxy metabolite.

When rats which had been pretreated with a high dose of diphenylhydantoin (80 mg/kg) for 5 days were given a single intravenous dose of phenobarbital (30 mg/kg): (a) There was no increase in the rate at which phenobarbital (PB) disappeared from the plasma or the tissues of pretreated rats. (b) The percentages of phenobarbital and p-hydroxyphenobarbital (free and conjugated) excreted in the urine were similar in both treated and control animals. However, the percentage of conjugated p-hydroxyphenobarbital excreted, was almost twice that of the control group. (c) Pretreatment with diphenylhydantoin (DPH) markedly increased bile flow rates. Therefore these rats excreted more PB than their controls. The biliary excretion of hydroxylated metabolites of PB (free and conjugated), was similar to that found in urine. Hydroxylation was not increased although, there was a significant elevation in the percentage of conjugated metabolite excreted. In a study to establish whether the main metabolites of diphenylhydantoin interfered with the metabolism of phenobarbital the following results were obtained: (a) Intravenous administration of DPH together with PB caused a two-fold increase in the half-life of phenobarbital elimination. (b) Intravenous administration of PB, to bile duct cannulated rats which had been pretreated for 5 days with DPH, caused a significant reduction in the excretion of hydroxylated phenobarbital in comparison with their control group. However, all the excreted DPH was present in the conjugated form. (c) The DPH pretreated rats had significantly lower cytochrome P-450 and mono-oxygenase activities in their hepatic microsomes than the pretreated controls, and higher UDP-glucuronyltransferase activity with DPH itself as the substrate.