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01-06-2007 | Original Article

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

Authors: Jan H. Beumer, Jeany M. Rademaker-Lakhai, Hilde Rosing, Michel J. X. Hillebrand, Tessa M. Bosch, Luis Lopez-Lazaro, Jan H. M. Schellens, Jos H. Beijnen

Published in: Cancer Chemotherapy and Pharmacology | Issue 6/2007

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.

Beumer JH, Rademaker-Lakhai JM, Rosing H, Lopez-Lazaro L, Beijnen JH, Schellens JH (2005) Invest New Drugs 23:429–436PubMedCrossRef

Beumer JH, Schellens JH, Beijnen JH (2005) Pharmacol Res 51:391–398PubMed

Boom R, Sol CJ, Salimans MM, Jansen CL, Wertheim-van Dillen PM, van der Noordaa J (1990) J Clin Microbiol 28:495–503PubMed

Brandon EF, Sparidans RW, Guijt KJ, Lowenthal S, Meijerman I, Beijnen JH, Schellens JH (2006) Invest New Drugs 24(1):3–14PubMedCrossRef

Coleman JP, White WB, Egestad B, Sjovall J, Hylemon PB (1987) J Biol Chem 262:4701–4707PubMed

D’Incalci M, Jimeno J (2003) Expert Opin Investig Drugs 12:1843–1853PubMedCrossRef

Garcia-Carbonero R, Supko JG, Maki RG, Manola J, Ryan DP, Harmon D, Puchalski TA, Goss G, Seiden MV, Waxman A, Quigley MT, Lopez T, Sancho MA, Jimeno J, Guzman C, Demetri GD (2005) J Clin Oncol 23:5484–5492PubMedCrossRef

Goldstein JA, Blaisdell J (1996) Meth Enzymol 272:210–218PubMed

Grasten SM, Juntunen KS, Poutanen KS, Gylling HK, Miettinen TA, Mykkanen HM (2000) J Nutr 130:2215–2221PubMed

10.

Huang CS, Luo GA, Huang ML, Yu SC, Yang SS (2000) Pharmacogenetics 10:539–544PubMedCrossRef

11.

Jeronimo C, Varzim G, Henrique R, Oliveira J, Bento MJ, Silva C, Lopes C, Sidransky D (2002) Cancer Epidemiol Biomarkers Prev 11:445–450PubMed

12.

Jin S, Gorfajn B, Faircloth G, Scotto KW (2000) Proc Natl Acad Sci USA 97:6775–6779PubMedCrossRef

13.

Kanzaki A, Takebayashi Y, Ren XQ, Miyashita H, Mori S, Akiyama S, Pommier Y (2002) Mol Cancer Ther 1:1327–1334PubMed

14.

van Kesteren C, de Vooght MM, Lopez-Lazaro L, Mathot RA, Schellens JHM, Jimeno JM, Beijnen JH (2003) Anticancer Drugs 14:487–502PubMedCrossRef

15.

Kuffel MJ, Reid JM, Ames MM (1997) Proc Am Assoc Cancer Res 38:4003

16.

MacLeod SL, Nowell S, Plaxco J, Lang NP (2000) Ann Surg Oncol 7:777–782PubMedCrossRef

17.

Minuzzo M, Marchini S, Broggini M, Faircloth G, D’Incalci M, Mantovani R (2000) Proc Natl Acad Sci USA 97:6780–6784PubMedCrossRef

18.

Moore BM, Seaman FC, Wheelhouse RT, Hurley LH (1998) J Am Chem Soc 120:2490–2491CrossRef

19.

Morales JJ (1999) Marine natural products chemistry of a Caribbean tunicate and a Palau sponge. Thesis, University of Illinois, Urbana

20.

Pommier Y, Kohlhagen G, Bailly C, Waring M, Mazumder A, Kohn KW (1996) Biochemistry 35:13303–13309PubMedCrossRef

21.

Rosing H, Hillebrand MJ, Jimeno JM, Gomez A, Floriano P, Faircloth G, Henrar RE, Vermorken JB, Cvitkovic E, Bult A, Beijnen JH (1998) J Mass Spectrom 33:1134–1140PubMedCrossRef

22.

Sata F, Sapone A, Elizondo G, Stocker P, Miller VP, Zheng W, Raunio H, Crespi CL, Gonzalez FJ (2000) Clin Pharmacol Ther 67:48–56PubMedCrossRef

23.

van Schaik RH, van der Heiden I, van den Anker JN, Lindemans J (2002) Clin Chem 48:1668–1671PubMed

24.

Schur BC, Bjerke J, Nuwayhid N, Wong SH (2001) Clin Chim Acta 308:25–31PubMedCrossRef

25.

Sparidans RW, Rosing H, Hillebrand MJ, Lopez-Lazaro L, Jimeno JM, Manzanares I, van Kesteren C, Cvitkovic E, van Oosterom AT, Schellens JHM, Beijnen JH (2001) Anticancer Drugs 12:653–666PubMedCrossRef

26.

Sreelekha TT, Ramadas K, Pandey M, Thomas G, Nalinakumari KR, Pillai MR (2001) Oral Oncol 37:593–598PubMedCrossRef

27.

Sullivan-Klose TH, Ghanayem BI, Bell DA, Zhang ZY, Kaminsky LS, Shenfield GM, Miners JO, Birkett DJ, Goldstein JA (1996) Pharmacogenetics 6:341–349PubMedCrossRef

28.

Verweij J (2005) J Clin Oncol 23:5420–5423PubMedCrossRef

29.

Villalona-Calero MA, Eckhardt SG, Weiss G, Hidalgo M, Beijnen JH, van Kesteren C, Rosing H, Campbell E, Kraynak M, Lopez-Lazaro L, Guzman C, Von Hoff DD, Jimeno J, Rowinsky EK (2002) Clin Cancer Res 8:75–85PubMed

30.

Wu X, Shi H, Jiang H, Kemp B, Hong WK, Delclos GL, Spitz MR (1997) Carcinogenesis 18:967–973PubMedCrossRef

Title: Metabolism of trabectedin (ET-743, Yondelis™) in patients with advanced cancer
Authors: Jan H. Beumer
Jeany M. Rademaker-Lakhai
Hilde Rosing
Michel J. X. Hillebrand
Tessa M. Bosch
Luis Lopez-Lazaro
Jan H. M. Schellens
Jos H. Beijnen
Publication date: 01-06-2007
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 6/2007
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-006-0342-2

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