Effect of ethanol on benzodiazepine disposition in dogs

Ethanol is known to enhance the central nervous system effects of benzodiazepine compounds, but the precise mechanism is still unknown. The present study was undertaken to determine the effect of ethanol on the disposition and elimination of commonly prescribed benzodiazepines and their principal metabolites. In the first set of studies, ethanol (3 gm/kg) or saline was given at two weekly intervals by gavage to the same male dogs weighing 15 to 25 kg. One hour after ethanol or saline ingestion, 100 mg of chlordiazepoxide (Librium), 1 mg/kg demoxepam (a metabolite of chlordiazepoxide), 1 mg/kg diazepam (Valium), or 1 mg/kg desmethyldiazepam (a metabolite of either demoxepam or diazepam) was given intravenously. Plasma samples were obtained for ethanol assay and for drug measurements by gas-liquid chromatography or high-performance liquid chromatography. Diazepam proved to have high systemic clearance, whereas demoxepam and desmethyldiazepam had low clearance; the clearance of chlordiazepoxide was intermediate between the two groups. Ethanol had no effect on the systemic clearance of either diazepam or chlordiazepoxide but reduced the systemic clearance of the metabolites. Demoxepam clearance decreased from 51.1 ± 8.1 (mean ± S.E.) ml/min to 24.96 ± 2.8 (p < 0.05), and desmethyldiazepam clearance dropped from 67.7 ± 14.7 ml/min to 36.9 ± 6.7 (p < 0.05). The hepatic elimination of high-clearance drugs given intravenously is dependent on hepatic blood flow, but the elimination of orally given drugs depends on enzyme activity. Therefore in the second set of studies diazepam and chlordiazepoxide were given orally. Ethanol (3 gm/kg) decreased the clearance of oral diazepam by 74% (p < 0.05) and that of chlordiazepoxide by 65% (p < 0.05). This reduction in clearance was accompanied by increased systemic bioavailability. These findings are consistent with the observation made by others that ethanol inhibits the microsomal oxidative enzyme system. They also explain, at least to some extent, the enhanced sedation resulting from combined ethanol-benzodiazepine administration and add to the understanding of ethanol and drug interactions.