Imipramine-cimetidine interaction: Impairment of clearance and enhanced absolute bioavailability

Six healthy volunteers each received imipramine on four occasions in random sequence, i.v. (12.5 mg) and p.o. (50 mg) in a drug-free state and i.v. and p.o. while taking cimetidine 300 mg every 6 hr. After i.v. doses, elimination half-life of imipramine was increased during cimetidine treatment (22.1 vs. 15.5 hr P < .02) as a result of decreased total metabolic clearance (623 vs. 1048 ml/min, P < .05) with no change in volume of distribution (17.2 vs. 19.8 liters/kg) or plasma protein binding (unbound percent, 17.7 vs. 16.5%). After single p.o. imipramine doses, peak imipramine blood levels achieved were greater during cimetidine therapy (34.4 vs. 19.3 ng/ml, P < .05) and area under the time/concentration curve was greatly increased (569 vs. 306 ng/ml x hr, P < .05). Desipramine, the biologically active metabolite of imipramine, was measurable only after p.o. doses. Desipramine area under the time/concentration curve was increased during cimetidine therapy after p.o. imipramine doses (274 vs. 152 ng/ml x hr, P < .05), suggesting that desipramine clearance was inhibited as well. Comparison of i.v. and p.o. imipramine doses indicated absolute bioavailability was 40.2% in the control state and increased to 75.3% (P < .05) during cimetidine treatment. Imipramine, with both impaired total metabolic clearance and enhanced bioavailability, in conjunction with increased accumulation of desipramine, would have marked increases in steadystate plasma concentration of both imipramine and desipramine with concurrent cimetidine therapy during chronic p.o. treatment.