Effect of short-term ethanol administration on lorazepam clearance

The disposition of chlordiazepoxide (Librium) and diazepam (Valium), compounds which are initially degraded by oxidative processes, differs from that of oxazepam (Serax) and lorazepam (Ativan, drugs which are inactivated by conjugation with glucuronic acid. Liver disease and cimetidine impair the elimination of the former agents, but not the latter two benzodiazepines. In addition, ethanol inhibits the metabolism of chlordiazepoxide and diazepam. The present studies were performed to determine the effect of short-term ethanol administration on glucuronidation and elimination of lorazepam in dogs and humans. Because, in dogs, lorazepam has a high extraction ratio (approximately 0.9) with an anticipated large presystemic elimination, the influence of ethanol on the presystemic (first-pass) elimination of lorazepam was determined. Administration of p.o. lorazepam to five healthy dogs 1 hr after i.v. saline or ethanol (3 gm/kg) reduced the presystemic elimination of lorazepam by 52% (p less than 0.05). In man, lorazepam has a low (approximately by 0.05) extraction ratio and only a small first-pass effect. Short-term administration of ethanol (0.8 gm/kg followed by 0.5 gm/kg p.o. every 5 hr for four doses) reduced i.v. lorazepam clearance by 18% (p less than 0.03). In dogs and man, ethanol did not significantly alter lorazepam t1/2, plasma protein binding, or distribution volume (Vd beta). The results suggest that short-term ethanol administration impairs the conjugation of lorazepam in dogs and man.