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

J Pharmacol Exp Ther. 1984 Jun;229(3):702-5.


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 less than .02) as a result of decreased total metabolic clearance (623 vs. 1048 ml/min, P less than .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 less than .05) and area under the time/concentration curve was greatly increased (569 vs. 306 ng/ml X hr, P less than .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 less than .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 less than .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 steady-state plasma concentration of both imipramine and desipramine with concurrent cimetidine therapy during chronic p.o. treatment.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Administration, Oral
  • Adult
  • Biological Availability
  • Cimetidine / administration & dosage
  • Cimetidine / blood*
  • Drug Interactions
  • Half-Life
  • Humans
  • Imipramine / administration & dosage
  • Imipramine / blood*
  • Injections, Intravenous
  • Kinetics


  • Cimetidine
  • Imipramine