RESUMEN
Cimetidine has been shown to inhibit oxidative metabolism of several drugs while sparing the glucuronidation pathways of drug metabolism. We studied the time-course of inhibition and recovery of cimetidine-inhibited chlordiazepoxide elimination in 7 healthy subjects. Chlordiazepoxide elimination was studied after cimetidine treatment for 1 and 30 days, and after withdrawing cimetidine for 48 h. The plasma clearance of chlordiazepoxide was reduced by 54% (p less than 0.001) after 24 h of cimetidine, by 57% (p less than 0.001) after 30 days of cimetidine and returned to normal after cimetidine was stopped for 48 h. In the absence of changes in volume of distribution, these changes resulted in proportional increases in the elimination half-life (t 1/2 beta) after 24 h and 30 days cimetidine treatment, and returned to pretreatment values after stopping cimetidine. In addition, the impaired chlordiazepoxide elimination was accompanied by inhibition of generation and subsequent elimination of N-desmethylchlordiazepoxide, the first metabolite of chlordiazepoxide metabolism. This study demonstrates a rapid inhibitory effect on chlordiazepoxide elimination, an absence of tolerance to this effect and a rapid reversal of this effect upon stopping cimetidine. These findings may have important therapeutic implications for patients receiving both drugs simultaneously.
Asunto(s)
Clordiazepóxido/metabolismo , Cimetidina/farmacología , Guanidinas/farmacología , Adulto , Clordiazepóxido/análogos & derivados , Clordiazepóxido/sangre , Femenino , Humanos , Cinética , MasculinoRESUMEN
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.