The metabolism and excretion of [14C]imipramine in an experimental hepatitis.
The effect of experimental hepatitis, induced by i.p. D-galactosamine, on the metabolism and excretion of [14C]imipramine in the rat is reported. The major consequence was an increase of the conjugated metabolites of imipramine excreted in urine, resulting in a four-fold increase in 2-hydroxyimipramine glucuronide and two-fold increases in 2-hydroxydesmethylimipramine glucuronide and 10-hydroxyimipramine glucuronide. The total excretion of 14C-labelled metabolites in urine of galactosamine-treated rats was 69% dose compared with 37% in untreated animals. Faecal excretion of [14C]imipramine metabolites was lowered from 68% dose in untreated animals to 27% in animals with induced hepatitis. Induction of a galactosamine hepatitis decreased markedly the biliary excretion of imipramine metabolites in bile duct-cannulated rats; 80% dose was excreted in bile in normal rats, and 35.5% in rats with hepatitis. Plasma clearance of imipramine, after i.v. dosage, was decreased by 60% and clearance of metabolites (excluding imipramine) by 40%, in galactosamine hepatitis; the pharmacokinetics changed from a two- to a single-compartment system reflecting decreased extraction and/or metabolism, by the liver. The clinical implications of these findings are discussed in relation to the hazard attending the use of imipramine in patients suffering from liver disease.
D000818:Animals; D001646:Bile / Q000032:analysis; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D005688:Galactosamine / Q000633:toxicity; D006520:Hepatitis, Animal / Q000378:metabolism*; D007099:Imipramine / Q000097:blood / Q000378:metabolism* / Q000652:urine; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D005688:Galactosamine; D007099:Imipramine