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


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.
Beumer
Jan H
JH
Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Louwesweg 6, 1066, Amsterdam, and Department of Biomedical Analysis, Faculty of Pharmaceutical Sciences, Utrecht University, The Netherlands. beumerjh@upmc.edu
Rademaker-Lakhai
Jeany M
JM
Rosing
Hilde
H
Hillebrand
Michel J X
MJ
Bosch
Tessa M
TM
Lopez-Lazaro
Luis
L
Schellens
Jan H M
JH
Beijnen
Jos H
JH
D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics*; D002845:Chromatography; D004149:Dioxoles / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D005243:Feces / Q000737:chemistry; D020719:Glucuronides / Q000032:analysis; D006801:Humans; D013058:Mass Spectrometry; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011110:Polymorphism, Genetic; D044005:Tetrahydroisoquinolines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D000077606:Trabectedin
D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D020719:Glucuronides; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin