Ethanol may enhance the
sedative effect of
benzodiazepines leading to greater
psychomotor impairment, but the mechanism is not clear. The present study was carried out to determine the effect of acute
ethanol ingestion on the disposition and elimination of
chlordiazepoxide (
Librium), a widely used
benzodiazepine. Five healthy, 22-39-year-old, male volunteers ingested
ethanol 0.8 g/kg as 25% in orange juice 1 h before
chlordiazepoxide 0.6 mg/kg was injected intravenously. To maintain plasma
ethanol concentrations of 50-150 mg!100 ml for 32 h additional
ethanol 0.5 g/kg was given orally every 5 h. Plasma clearance of
chlordiazepoxide fell from 26.6 +/- 2.6 ml/min (mean +/- SD) without
ethanol to 16.6 +/- 3.1 ml/min (P less than 0.05) after
ethanol. There was no change in the volume of distribution and therefore the elimination half-life was prolonged from 7.1 +/- 1.9 h to 11.8 +/- 6.0 h (P less than 0.05) after
ethanol.
Ethanol also lowered the plasma binding of
chlordiazepoxide from 94.7 +/- 0.6% to 93.4 +/- 1.3% (P less than 0.05). The plasma clearance of unbound
chlordiazepoxide fell from 468 +/- 51 ml/min to 264 +/- 98 ml/min (P less than 0.05) after
ethanol. The plasma level of the metabolite desmethylchlordiazepoxide was higher and its elimination slower after
ethanol. Thus using a pharmacokinetic approach this study has demonstrated that short-term
ethanol ingestion in moderate doses impairs the elimination of
chlordiazepoxide and accounts, at least partly, for the greater sedation that results when
ethanol is taken concomitantly.