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Flumazenil disposition and elimination in cirrhosis.

Flumazenil, a new and specific benzodiazepine antagonist that appears to be free of intrinsic pharmacologic action, is extensively metabolized by oxidative processes and represents a high-clearance drug. Consequently, it could be anticipated that hepatic disease affects the elimination and oral bioavailability of flumazenil. Therefore, the pharmacokinetics of flumazenil was evaluated in eight patients who had moderate cirrhosis and in eight age-matched healthy volunteers after a single oral dose (30 mg) and after an intravenous dose (2 mg). The mean half-life (t1/2) was 0.8 versus 1.4 hours (p = 0.003) and total plasma clearance was 1201 versus 705 ml per minute (p = 0.009) for control subjects versus patients with cirrhosis. Bioavailability increased from the normal 28% to 65% (p = 0.001) in patients with hepatic dysfunction. Routine liver tests did not correlate with the elimination of flumazenil in individual patients. It can be concluded that elimination of flumazenil is impaired in patients who have stable alcoholic cirrhosis. Despite the relative wide margin of safety of flumazenil, somewhat lower doses could be effective in such patients if long-term oral use is anticipated.