Influence of extrahepatic cholestasis on metabolism and biliary excretion of imipramine.

Seven days after bile duct ligation, rat receiving 80 mg of 14-C-imipramine/kg i.p. excrete less than 2 per cent of the dose as total drug (imipramine plus metabolites) within 2h through a bile fistula. In rats without cholestasis, the biliary excretion accounts for 15 per cent of the dose. The percentage of the dose found in liver, lung, brain, and blood does not differ from that found in bile fistula rats without prior bile duct ligation. The conjugates of the hydroxylated imipramine metabolites account for 33 per cent of the total drug excreted through bile after bile duct ligation as compared with 88 per cent in rats without bile duct ligation. The remaining 67 per cent of total drug are excreted as desmethylimipramine, imipramine-N-oxide and imipramine at about equal parts. Hepatic microsomal N-demethylating enzyme activity after bile duct ligation is decreased as well as the content of microsoma cytochrome P-450. A concomittant complentary appearance of the metabolically inactive cytochrome P-420 is observed.