Abstract
Trabectedin (ET-743, Yondelis) is a novel anti-cancer drug currently undergoing phase II-III evaluation, that has shown remarkable activity in pre-treated patients with soft tissue sarcoma. Despite extensive pharmacokinetic studies, the human disposition and metabolism of trabectedin remain largely unknown. We aimed to determine the metabolic profile of trabectedin and to identify its metabolites in humans. We analysed urine and faeces (the major excretory route) from eight cancer patients after a 3 or 24 h intravenous administration of [14C]trabectedin. Using liquid chromatography with tandem quadrupole mass spectrometric detection (LC-MS/MS) and radiochromatography with off-line radioactivity detection by liquid scintillation counting (LC-LSC), we characterised the metabolic profile in 0-24 h urine and 0-120 h faeces. By radiochromatography, a large number of trabectedin metabolites were detected. Incubation with beta-glucuronidase indicated the presence of a glucuronide metabolite in urine. Trabectedin, ET-745, ET-759A, ETM-259, ETM-217 (all available as reference compounds) and a proposed new metabolite coined ET-731 were detected using LC-MS/MS. The inter-individual differences in radiochromatographic profiles were small and did not correlate with polymorphisms in drug-metabolising enzymes (CYP2C9, 2C19, 2D6, 2E1, 3A4, GST-M1, P1, T1 and UGT1A1 2B15) as determined by genotyping. Trabectedin is metabolically converted to a large number of compounds that are excreted in both urine and faeces. In urine and faeces we have confirmed the presence of trabectedin, ET-745, ET-759A, ETM-259, ETM-217 and ETM-204. In addition we have identified a putative new metabolite designated ET-731. Future studies should be aimed at further identification of possible metabolites and assessment of their activity.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
