ABSTRACT
Imipramine (10 mg/kg, p.o.) administered to male Wistar rats (133-178 g) twice daily for 3 weeks more than halved the control rate of body weight gain. A bile fistula was inserted after this period and 14C-imipramine (10 mg/kg, p.o.) was administered 14-18 hr after the final scheduled dose. Biliary excretion of radioactivity during the subsequent 50 min was decreased to 16% of control. Higher levels of gastrointestinal radioactivity (mainly in the stomach lumen) indicated a slower imipramine absorption rate in the subacute group. Liver metabolite ratios revealed that the treatment group had decreased rates of 2-hydroxylation and 10-hydroxylation, but not demethylation, of imipramine. After incubation of the 25-50 min bile sample with glusulase, bile-to-liver ratios of metabolites indicated a lower entry rate of imipramine, desmethylimipramine and 2-hydroxydesmethylimipramine, but not of 2-hydroxyimipramine or 10-hydroxyimipramine, into bile of the subacute imipramine group.
Subject(s)
Imipramine/metabolism , Administration, Oral , Animals , Bile/metabolism , Biotransformation , Body Weight/drug effects , Imipramine/administration & dosage , Imipramine/pharmacology , Intestinal Absorption , Kinetics , Liver/metabolism , Male , Rats , Time FactorsSubject(s)
Imipramine/metabolism , Stomach/physiology , Animals , Bile/metabolism , Imipramine/urine , Intestinal Absorption , Male , RatsABSTRACT
The toxicity of pentobarbital was examined in male Wistar rats pretreated with a non-toxic dose of imipramine (10 mg/kg, po). Pentobarbital (70 mg/kg, ip) lethality was enhanced up to 6 hr after imipramine administration, and pentobarbital (45 mg/kg, ip) sleeping time was prolonged up to 12 hr after imipramine. Physiological measurements showed that imipramine pretreatment 2 hr prior to pentobarbital (70 mg/kg, ip) enhanced barbiturate depression in mean blood pressure, oxygen consumption and respiration rate, but not in heart rate or back skin temperature. Analysis of brain radioactivity after [14C] pentobarbital indicated that these effects of imipramine were not solely the result of inhibition of liver metabolism.
Subject(s)
Imipramine/pharmacology , Pentobarbital/toxicity , Animals , Blood Pressure/drug effects , Brain/metabolism , Drug Administration Schedule , Drug Synergism , Heart Rate/drug effects , Imipramine/blood , Male , Oxygen Consumption/drug effects , Pentobarbital/metabolism , Rats , Respiration/drug effects , Skin Temperature/drug effects , Sleep/drug effects , Time FactorsABSTRACT
The pharmacokinetics of [14C]imipramine (10 mg kg minus 1) were tested in male Wistar rats for interaction with thioridazine (16 mg kg minus 1) or diazepam (10 mg kg- minus 1). All drugs were administered orally with the test substances being given 40 min before [14C]imipramine dosing. Bile and urine were collected for 90 min after the radioactive drug was given. The animals were then killed and the tissues removed. Thioridazine reduced the excretion of radioactivity into the bile and urine, and increased the weight of the contents within the gastrointestinal tract. These effects were interpreted as being mainly due to a reduction in gastrointestinal motility resulting in a slower stomach emptying of [14C]imipramine. No effect on metabolism was detected. Diazepam pretreatment reduced the concentration ratio of radioactivity in the small intestinal contents to that of plasma, but did not alter the tissue distribution, metabolism or excretion of [14C]imipramine.
