EFFECTS OF DIAZEPAM ON BILIARY-EXCRETION OF DIPHENYLHYDANTOIN IN RAT

Abstract

Studies were performed to examine the effects of diazepam (DZP) on the biliary excretion of diphenylhydantoin (DPH, phenytoin) in the rat. One hour pretreatment with DZP (150 mg/kg i.p. or 10 mg/kg i.v.) markedly suppressed the rates as well as the cumulative amounts of radioactivity excreted in bile after administration of 14C-DPH (70, 35 or 10 mg/kg i.v.). No changes in bile flow were apparent and the decreases in biliary excretion were not accompanied by increases in the urinary elimination of the drug or its metabolites. Disappearance of DPH from plasma and tissue were also reduced, and at 4 and 6 h after DPH administration higher plasma and tissue concentrations were encountered in the DZP-treated group. The possible mechanisms by which DZP pretreatment altered the biliary excretion and the tissue distribution of DPH were examined; studies in vitro were correlated with the in vivo findings. DPH hepatic uptake and storage were apparently unaffected by DZP treatment, but liver/bile concentration ratios were suppressed. A direct competition between the 2 drugs for biliary transport was not evident. Liver microsomes from rats treated with DZP metabolized DPH in vitro less effectively than those from control rats. The metabolism of DPH was more markedly inhibited by the direct addition of DZP to the incubation mixtures in concentrations greater than 0.05 mM. The effect of DZP on the metabolism of DPH appears to be responsible for most of the observed effects although other mechanisms, including a direct effect on hepatocyte function, cannot be completely ruled out.