| Abstrakt: |
The metabolism of chlorpromazine (CPZ), imipramine (IP), and imipramine-N-oxide (IPNO) was studied in microsomal preparations of various rat tissues in vitro and in the isolated perfused liver. A technique for a total hepatectomy in the rat has been developed, allowing estimations of extrahepatic and hepatic drug metabolism in vivo. CPZ is converted to its sulfoxide and other metabolites in the liver and, to a minor degree, in many extrahepatic organs except brain and skin. Whole blood of several species shows a remarkable sulfoxidizing activity which can be traced to the hemoglobin and is likely to represent a heme catalysis. IP is metabolized in the liver in vitro and, to a very minor extent, in lung and kidney. Blood, brain and many other extrahepatic tissues do not metabolize this drug in vitro. However, gastro-intestinal contents of rats and humans demethylate IP to Desmethylimipramine (DMI). This is likely to be the reason for a hepatic/ extrahepatic metabolism ratio of 53/47 measured in sham operated and totally hepatectomized rats. The occurrence of IPNO metabolism in extrahepatic tissues in vitro was confirmed in vivo with hepatectomized rats. The hepatic/extrahepatic ratio is 10/90. The course of IPNO metabolism, compartmental distribution and biliary excretion of the drug and its metabolites was studied in rat liver perfusion experiments. Immediate partial conversion of IPNO to IP and DMI by hemoglobin was confirmed by perfusion experiments without the liver, and liver perfusions with hemoglobin-free perfusates. [ABSTRACT FROM AUTHOR] |
