BIOTRANSFORMATION OF TOPOTECAN IN THE ISOLATED-PERFUSED RAT-LIVER - IDENTIFICATION OF 3 NOVEL METABOLITES

This study evaluates the metabolism of the anticancer drug topotecan ( TPT) in the isolated perfused rat liver of male Wistar-rats. Using a s ensitive high-performance liquid chromatography method, in bile TPT, i ts ring-opened hydroxycarboxylate form and three new metabolites could be quantified. Enzymatic hydrolysis of the metabolites with beta-gluc uronidase and mass spectroscopy revealed the existence of glucuronidat ed TPT as well as unconjugated and glucuronidated bidesmethyl TPT. Bil iary secretion of glucuronidated N-bidesmethyl TPT was fast reaching a maximum already after 15 min(30.6 +/- 15.1 pmol/g liver.min), whereas secretion of TPT, topotecan glucuronide and N-bidesmethyl TPT was del ayed (maximum at 30 min: 431 +/- 19, 6.4 +/- 2.1 and 12.7 +/- 2.7 pmol /g liver.min, respectively). No release of TPT metabolites into the pe rfusate was detected. The amount of TPT, TPT glucuronide, N-bidesmethy l TPT and N-bidesmethyl TPT glucuronide excreted into bile during 60 m in of perfusion was 2.10 +/- 0.483 %, 0.031 +/- 0.006 %, 0;058 +/- 0.0 13 % and 0.108 +/- 0.012 % of TPT cleared from the perfusate over 60 m in respectively. In conclusion we could identify three novel TPT metab olites, however, their overall metabolism in the rat liver is low.