Cancer Chemotherapy and Pharmacology

, Volume 59, Issue 6, pp 825–837

Metabolism of trabectedin (ET-743, Yondelis™) in patients with advanced cancer

Authors

    • Department of Pharmacy and PharmacologySlotervaart Hospital/The Netherlands Cancer Institute
    • The Hillman Cancer Center, Research Pavilion, G.27d, 5117 Centre Avenue
  • Jeany M. Rademaker-Lakhai
    • Departments of Medical Oncology and Experimental TherapyAntoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute
  • Hilde Rosing
    • Department of Pharmacy and PharmacologySlotervaart Hospital/The Netherlands Cancer Institute
  • Michel J. X. Hillebrand
    • Department of Pharmacy and PharmacologySlotervaart Hospital/The Netherlands Cancer Institute
  • Tessa M. Bosch
    • Department of Pharmacy and PharmacologySlotervaart Hospital/The Netherlands Cancer Institute
  • Luis Lopez-Lazaro
    • PharmaMar, Human Pharmacology, Colmenar Viejo
  • Jan H. M. Schellens
    • Departments of Medical Oncology and Experimental TherapyAntoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute
    • Department of Biomedical Analysis, Division of Drug Toxicology, Faculty of Pharmaceutical SciencesUtrecht University
  • Jos H. Beijnen
    • Department of Pharmacy and PharmacologySlotervaart Hospital/The Netherlands Cancer Institute
    • Department of Biomedical Analysis, Division of Drug Toxicology, Faculty of Pharmaceutical SciencesUtrecht University
Original Article

DOI: 10.1007/s00280-006-0342-2

Cite this article as:
Beumer, J.H., Rademaker-Lakhai, J.M., Rosing, H. et al. Cancer Chemother Pharmacol (2007) 59: 825. doi:10.1007/s00280-006-0342-2
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Abstract

Purpose

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.

Methods

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.

Results

By radiochromatography, a large number of trabectedin metabolites were detected. Incubation with β-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.

Conclusions

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.

Keywords

TrabectedinMetabolismExcretionGenotypingHuman

Copyright information

© Springer-Verlag 2006