Uptake, Metabolism and Excretion of Desmethylimipramine and its Metabolites in the Isolated Perfused Rat Liver

The isolated perfused rat liver was used in order to study the metabolism of the tricyclic antidepressant drug, desmethylimipramine (DMI), which is metabolized by oxidation and subsequent conjugation. DMI labelled with tritium in a position in which it is not eliminated by metabolism, was used. Extraction procedures were developed which allowed a separation of DMI and its hydroxyl‐ated and conjugated metabolites. DMI and its metabolites were measured in perfusate plasma, bile and liver. DMI disappeared quickly from the plasma and reappeared in high concentrations in liver and bile. The drug was highly bound to proteins in perfusate plasma, while the conjugated metabolites were not bound at all. The red blood corpuscles contained approximately ten times higher concentrations of DMI than perfusate plasma but no conjugated metabolites. Only small amounts of unconjugated hydroxylated metabolites were found in perfusate plasma, liver and bile in contrast to the conjugated metabolites which occurred in considerable amounts in perfusate plasma and bile. DMI was bound to the microsomal fraction of the liver cell. The conjugated metabolites appeared mainly in the cytoplasm of the liver cell.