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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.
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.