The prevention by (+)-Cyanidanol-3 of hepatitis-induced changes in the disposition of imipramine in the rat.

The administration of (+)-Cyanidanol-3 [+)-catechin) to the rat using a subchronic dosing regime based on that currently used in the therapy of acute viral hepatitis in man, largely prevented the changes in the disposition of a single dose of [14C]imipramine hydrochloride induced by the hepatotoxin, D-(+)-galactosamine hydrochloride in rats. Complete return to normal pharmacokinetics was not attained due to interaction between (+)-Cyanidanol-3 and imipramine. Biliary excretion of imipramine metabolites was 79.3% of the dose in control rats. This was reduced to 69.3 and 39.8% by the separate administration of (+)-catechin and galactosamine respectively. Concurrent administration of (+)-Cyanidanol-3 and galactosamine resulted in 64.8% of the imipramine dose appearing in bile. These results were reflected in changes in faecal and renal excretion of imipramine metabolites in surgically unmodified rats in which galactosamine injection caused an elevation of urinary excretion from 31.0 to 69.8% of the imipramine dose. Concurrent Cyanidanol administration reduced the effect of galactosamine so that only 46.9% was excreted in urine. These changes were due to decreased biliary excretion and increased renal excretion of the glucuronide conjugates of 2-hydroxyimipramine, 2-hydroxydesmethylimipramine and 10-hydroxyimipramine. None of the treatments used impaired the overall ability of the rat to metabolize imipramine, although the plasma clearance of imipramine was reduced by 42% as a result of galactosamine administration and by 21% during treatment with (+)-catechin alone or combined catechin and galactosamine treatment.