INHIBITION OF DIAZEPAM METABOLISM BY FLUVOXAMINE - A PHARMACOKINETIC STUDY IN NORMAL VOLUNTEERS

The effect of fluvoxamine on the pharmacokinetics of diazepam and meta bolically derived N-desmethyldiazepam was investigated in eight health y volunteers. Each subject received a single oral dose of diazepam (10 mg) in a control session and on the fourth day of a 16-day treatment with fluvoxamine maleate (100 to 150 mg daily). Compared with the cont rol session, concurrent fluvoxamine intake was associated with increas ed mean peak plasma diazepam concentrations (from 108 to 143 ng/ml, ge ometric means, difference not significant), with a marked reduction in apparent oral diazepam clearance (from 0.40 to 0.14 ml/min/kg; p < 0. 01) and with a prolongation in diazepam half-life (from 51 to 118 hour s; p < 0.01). Although peak plasma N-desmethyldiazepam levels were sim ilar in the two sessions, the time required for the metabolite to reac h a peak was longer during fluvoxamine intake than in the control sess ion (206 versus 62 hours; p < 0.01). N-Desmethyldiazepam area under th e plasma concentration-time curve values were also significantly incre ased during fluvoxamine treatment. These data suggest that fluvoxamine inhibits the biotransformation of diazepam and its active N-demethyla ted metabolite. The magnitude of this interaction is likely to have co nsiderable clinical significance.