title: Imipramine treatment alters the pharmacokinetics and pharmacodynamics of diazepam.
abstract: This report describes observations of the relationship between the pharmacokinetics and pharmacodynamics of diazepam (7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one ; 5 mg/kg) during the concomitant administration of diazepam and imipramine hydrochloride (5-[3-(dimethylamino)propyl]-10,11-dihydro-5H-dibenz[b,f]azepine monohydrochloride; 20 and 50 mg/kg) to rats. We measured plasma, brain, and liver concentrations of diazepam and its metabolites in rats by high-performance liquid chromatography. The concomitant use of imipramine hydrochloride increased diazepam and desmethyldiazepam concentrations, but decreased temazepam and oxazepam concentrations in rat plasma. Diazepam plasma protein binding was unaltered. The liver concentrations of diazepam and its metabolites showed similar changes in their plasma concentrations. The concomitant use of imipramine hydrochloride increased the concentrations of diazepam and its metabolites in the brain. We also studied the effect of benzodiazepines on convulsions induced by pentylenetetrazole (6,7,8,9-tetrahydro-5H-tetrazolo[1,5-a] azepine; 135 mg/kg) in rats. The concomitant use of imipramine hydrochloride led to an increased antipentylenetetrazole effect of diazepam. This result is in accordance with the findings on brain concentrations of diazepam and its metabolites.
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects; D003975:Diazepam / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D004347:Drug Interactions; D007099:Imipramine / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D003708:Nordazepam / Q000494:pharmacology; D010076:Oxazepam / Q000494:pharmacology; D010433:Pentylenetetrazole / Q000037:antagonists & inhibitors; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains; D013693:Temazepam / Q000097:blood
chemical_list: D001798:Blood Proteins; D003708:Nordazepam; D010076:Oxazepam; D013693:Temazepam; D007099:Imipramine; D003975:Diazepam; D010433:Pentylenetetrazole