Interaction of cimetidine with the triazolobenzodiazepines alprazolam and triazolam

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Abstract
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, PPP<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 drugs.

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