The influence of cimetidine on the pharmacokinetics of alprazolam and triazolam, two triazolobenzodiazepines metabolized by hepatic microsomal oxidation, was evaluated in a series of healthy volunteers. Subjects ingested single 1.0 mg dose of alprazolam or 0.5 mg doses of triazolam on two occasions, with and without concurrent administration of cimetidine (300 mg) every 6h. For alprazolam, which has a low hepatic clearance and low extraction ratio, cimetidine significantly impaired total metabolic clearance (1.05 versus 1.66 ml/min/kg, P<0.005), resulting="" in="" significantly="" prolonged="" elimination="" half-life="" (16.6="" versus="" 12.4h,="">P<0.005). for="" triazolam,="" which="" has="" higher="" hepatic="" clearance="" and="" an="" intermediate="" extraction="" ratio,="" total="" clearance="" was="" reduced="" by="" cimetidine="" (3.9="" versus="" 5.9="" ml/min/kg),="" causing="" a="" significant="" increase="" in="" total="" area="" under="" the="" plasma="" concentration="" curve="" (25="" versus="" 38="" ng/ml="" x="" h,="">P<0.02). however,="" elimination="" half-life="" of="" triazolam="" was="" not="" influenced="" by="" cimetidine="" (3.3="" versus="" 3.2="" h),="" indicating="" that="" the="" reduction="" in="" clearance="" was="" manifested="" as="" increased="" systemic="" availability.="" thus,="" cimetidine="" impairs="" the="" clearance="" of="" both="" alprazolam="" and="" triazolam,="" but="" the="" consequences="" of="" the="" kinetic="" change="" are="" different="" because="" of="" the="" differing="" hepatic="" extraction="" profiles="" of="" the="" two="">