ISOLATION, PURIFICATION AND BIOLOGICAL-ACTIVITY OF MAJOR DOCETAXEL METABOLITES FROM HUMAN FECES

We have developed a procedure suited for the isolation of metabolites of docetaxel (Taxotere) from human feces. The compounds were extracted from the feces with diethyl ether and further purified by (semiprepar ative) HPLC. Four metabolic products were obtained in submilligram qua ntities. Analytical HPLC with photodiode array detection showed that t he purity of each compound was higher than 98%. Their structures have been characterized by UV absorption and FAB/MS. All four compounds wer e oxidation products of the tert-butyl group attached to the C13-side chain, and corresponded to structures identified previously. The purif ied products were used for evaluating their cytotoxic activities again st a human ovarian cancer (A2780) and a rat colon cancer (CC531) cell line, and their myelosuppressive effects in a hematopoietic progenitor toxicity assay. Although distinctions in biological activities betwee n the compounds were evident, all metabolites showed a marked reductio n in both cytotoxic and myelotoxic properties.