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Subacute imipramine: changes in single dose pharmacokinetics in rats
Archives Internationales De Pharmacodynamie Et De Therapie
|January 1, 1977
Summary
Subacute imipramine treatment in rats significantly reduced body weight gain and slowed imipramine absorption. This led to decreased biliary excretion and altered hepatic metabolism of imipramine and its metabolites.
Area of Science:
- Pharmacology
- Toxicology
- Drug Metabolism
Background:
- Imipramine is a tricyclic antidepressant with complex pharmacokinetic properties.
- Understanding the impact of chronic administration on imipramine's absorption, distribution, metabolism, and excretion (ADME) is crucial for clinical application.
Purpose of the Study:
- To investigate the effects of subacute imipramine administration on the pharmacokinetics and biliary excretion of imipramine in rats.
- To elucidate alterations in imipramine metabolism and its entry into bile following chronic treatment.
Main Methods:
- Male Wistar rats received imipramine (10 mg/kg, p.o.) twice daily for 3 weeks.
- A bile fistula was surgically prepared, and 14C-imipramine was administered.
- Biliary excretion of radioactivity, gastrointestinal radioactivity, and liver metabolite profiles were analyzed.
- Metabolite analysis in bile after glusulase incubation was performed.
Main Results:
- Subacute imipramine treatment significantly reduced body weight gain.
- Biliary excretion of radioactivity was decreased to 16% of control.
- Slower imipramine absorption was indicated by higher gastrointestinal radioactivity.
- Liver metabolite ratios showed decreased 2-hydroxylation and 10-hydroxylation rates.
- Lower entry rates of imipramine, desmethylimipramine, and 2-hydroxydesmethylimipramine into bile were observed.
Conclusions:
- Subacute imipramine administration impairs imipramine absorption and reduces its biliary excretion in rats.
- Chronic imipramine treatment alters hepatic hydroxylation pathways and affects the biliary transport of key imipramine metabolites.