Skip to main content

Advertisement

Log in

In vitro characterization of the human biotransformation and CYP reaction phenotype of ET-743 (Yondelis®, Trabectidin®), a novel marine anti-cancer drug

  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

ET-743 is a potent marine anti-cancer drug and is currently being investigated in phase I and II clinical trials, e.g. in combination with other anti-cancer agents. To assess the biotransformation and CYP reaction phenotype and their potential implications for human pharmacology and toxicology, the in vitro metabolism of ET-743 was characterized using incubations with human liver preparations, cytochrome P450 (CYP) and uridine diphosphoglucuronosyl transferase (UGT) supersomes.

CYP supersomes and liver microsomes showed that ET-743 was metabolized mainly by CYP3A4, but also by CYP2C9, 2C19, 2D6, and 2E1. ET-743 showed the highest affinity for CYP3A4 and the highest maximal metabolic rate for CYP2D6 among the CYPs shown to metabolize ET-743. In addition, the K m value of ET-743 in female microsomes was significantly lower compared to male microsomes, while the Vmax values did not differ. ET-743 glucuronidation, catalyzed by UGT2B15, was observed in microsomes and S9 fraction. In addition, conjugation by glutathione-S-transferase and no sulphation was observed for ET-743 in cytosol and S9 fraction. ET-743 was more extensively metabolized when CYP activity was combined with phase II enzymes UGT and glutathione-S-transferase (GST), indicating that CYP, UGT, and GST simultaneously metabolize ET-743 in the S9 fraction.

These results provide evidence that CYP3A4 has a major role in the metabolism of ET-743 in vitro with additional involvement of CYP2C9, 2C19, 2D6, and 2E1. Furthermore, ET-743 is conjugated by UGT and GST. This information could be important for interpretation of the pharmacokinetic data of clinical trials and prediction of drug-drug interactions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Jimeno JM: A clinical armamentarium of marine-derived anti-cancer compounds. Anticancer Drugs 13 (suppl 1):S15–S19, 2002

    CAS  PubMed  Google Scholar 

  2. Rinehart KL, Gravalos LG, Faircloth G, Jimeno J: Ecteinascidin (ET-743): Preclinical antitumor development of a marine derived natural product (abstract). Proc Am Assoc Cancer Res 36:2322, 1995

    Google Scholar 

  3. Jimeno JM, Faircloth G, Cameron L, Meely K, Vega E, Gómez A, Fernández Sousa-Faro JM, Rinehart K: Progress in the acquisition of new marine-derived anticancer compounds: development of Ecteinascidin-743 (ET-743). Drugs of the Future 21:1155–1165, 1996

    CAS  Google Scholar 

  4. D'Incalci M, Erba E, Damia G, Galliera E, Carassa L, Marchini S, Mantovani R, Tognon G, Fruscio R, Jimeno J, Faircloth GT: Unique features of the mode of action of ET-743. The Oncologist 7:201–216, 2002

    Article  Google Scholar 

  5. van Kesteren Ch, de Vooght MMM, López-Lázaro L, Mathôt RAA, Schellens JHM, Jimeno JM, Beijnen JH: Yondelis® (trabectedin, ET-743): The development of an anticancer agent of marine origen. Anticancer Drugs 14:487–502, 2003

    Google Scholar 

  6. Demetri GD, Manola J, Harmon D, Maki RG, Seiden MV, Supko JG, Ryan DP, Puchlaski TA, Goss G, Merriam P, Waxman A, Slater S, Potter A, Quigley MT, Lopez T, Sancho MA, Guzman C, Jimeno J, Garcia-Carbonero R: Ecteinascidin-743 (ET-743) induces durable responses and promising 1-year survival rates in soft tissue sarcomas (STS): Final results of phase II and pharmacokinetic studies in the U.S.A. (abstract). Proc Am Soc Clin Oncol 20:1406, 2001

    Google Scholar 

  7. Zelek L, Yovine A, Brain E, Turpin F, Taamma A, Riofrio M, Spielmann M, Jimeno J, Cvitkovic E: Preliminary results of phase II study of Ecteinascidin-743 with the 24 h continuous infusion Q3 weeks schedule in pretreated advanced/metastatic breast cancer patients (abstract). In: Proc 11th NCI-EORTC-AACR Symposium on New Drugs in Cancer Therapy, Amsterdam, The Netherlands: 2000 p. 85a

    Google Scholar 

  8. Aune GJ, Furuta T, Pommier Y: Ecteinascidin-743: A novel anticancer drug with a unique mechanism of action. Anticancer Drugs 13:545–555, 2002

    Article  CAS  PubMed  Google Scholar 

  9. Reid JM, Kuffel MJ, Ruben SL, Morales JJ, Rinehart KL, Squillace DP, Ames MM: Rat and human liver cytochrome P-450 isoform metabolism of Ecteinascidin 743 does not predict gender-dependent toxicity in humans. Clin Cancer Res 8:2952–2962, 2002

    CAS  PubMed  Google Scholar 

  10. Sparidans RW, Rosing H, Hillebrand MJX, López-Lázaro L, Jimeno JM, Manzanares I, van Kesteren Ch, Cvitkovic E, van Oosterom AT, Schellens JHM, Beijnen JH: Search for metabolites of ecteinascidin 743, a novel, marine-derived, anti-cancer agent, in man. Anticancer Drugs 12:653–666, 2001

    CAS  PubMed  Google Scholar 

  11. Curry SH: Chapter 2. In: Drug disposition and pharmaconkinetics with a consideration of pharmacological and clinical relationships. Blackwell Scientific Publications, Oxford, 1974, pp. 42–48

    Google Scholar 

  12. Gibson GG, Skett P: Chapter 1. In Introduction to drug metabolism. Blackie Academic and Professional, London, 1994, pp. 1–34

    Google Scholar 

  13. www.gentest.com. Gentest, a Becton and Dickinson company. (accessed July 2003).

  14. Crespi CL, Miller VP: The use of heterolously expressed drug metabolizing enzymes—State of the art and prospects for the future. Pharmacol Ther 84:121–131, 1999

    Article  CAS  PubMed  Google Scholar 

  15. Venkatakrishnan K, von Moltke LL, Court MH, Harmatz JS, Crespi CL, Greenblatt DJ: Comparison between cytochrome P450 (CYP) content and relative activity approaches to scaling from cDNA-expressed CYPs to human liver microsomes: Ratios of accessory proteins as sources of discrepancies between the approaches. Drug Metab Dispos 28:1493–1504, 2000

    CAS  PubMed  Google Scholar 

  16. Störmer W, von Moltke LL, Greenblatt DJ: Scaling drug biotransformation data from cDNA-expressed cytochrome P-450 to human liver: A copmparison of relative activity factors and human liver abundance in studies of mirtazapine metabolism. J Pharmacol Exp Ther 295:793–801, 2000

    PubMed  Google Scholar 

  17. van Kesteren Ch, Cvitkovic E, Taamma A, López-Lázaro L, Jimeno JM, Guzman C, Mathôt RAA, Schellens JHM, Misset J-L, Brian E, Hillebrand MJX, Rosing H, Beijnen JH: Pharmacokinetics and pharmacodynamics of the novel marine-derived anticancer agent ecteinascidin 743 in a phase I dose-finding study. Clin Cancer Res 6:4725–4732, 2000

    PubMed  Google Scholar 

  18. Puchalski TA, Ryan DP, Garcia-Carbonero R, Demetri GD, Butkiewicz L, Harmon D, Seiden MV, Maki RG, López-Lázaro L, Jimeno J, Guzman C, Supko JG: Pharmacokinetics of ecteinascidin 743 administred ad a 24-h continuous intravenous infusion to adult patients with soft tissue sarcomas: Associations with clinical characteristics, pathophysiological variables and toxicity. Cancer Chemother Pharmacol 50:309–319, 2002

    Article  CAS  PubMed  Google Scholar 

  19. Obach RS, Baxter JG, Liston TE, Silber BM, Jones BC, MacIntyre F, Rance DJ, Wastall P: The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data. J Pharamcol Exp Ther 283:46–58, 1997

    CAS  Google Scholar 

  20. www.gentest.com/human_p450_database. Gentest Cytochrome P450 database. (accessed January 2003)

  21. Wienkers LC, Wynalda MA: Multiple cytochrome P450 enzymes responsible for the oxidative metabolism of the substituted (S)-3-phenylpiperidine, (S, S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride, in human liver microsomes. Drug Metab Dispos 30:1372–1377, 2002

    Article  CAS  PubMed  Google Scholar 

  22. Ko JW, Desta Z, Soukhova NV, Tracy T, Flockhart DA: in vitro inhibition of the cytochrome P450 (CYP450) system by the antiplatelet drug ticlopidine: Potent effect on CYP2C19 and CYP2D6. Br J Clin Pharmacol 49:343–351, 2000

    CAS  Google Scholar 

  23. Zhou S, Paxton JW, Tingle MD, Kestell P: Identification of the human liver cytochrome P450 isoenzyme responsible for the 6-methylhydroxylation of the novel anticancer drug 5,6-dimethylxanthenone-4-acetic acid. Drug Metab Dispos 28:1449–1456, 2000

    CAS  PubMed  Google Scholar 

  24. Kumar GN, Dykstra J, Roberts EM, Jayanti VK, Hickman D, Uchic J, Yao Y, Surber B, Thomas S, Granneman GR: Potent inhibition of the cytochrome P-450 3A-mediated human liver microsomal metabolism of a novel HIV protease inhibitor by ritonavir: A positive drug-drug interaction. Drug Metab Dispos 27:902–908, 1999.

    CAS  PubMed  Google Scholar 

  25. Rodrigues AD: Integrated cytochrome P450 reaction phenotyping. Attempting to bridge the gap between cDNA-expressed cytochromes P450 and native human liver microsomes. Biochem Pharmacol 57:465–480, 1999

    CAS  PubMed  Google Scholar 

  26. Lu AYH, Wang RW, Lin JH: Cytochrome P450 in vitro reaction phenotyping: A re-evaluattion of approaches used for P450 isofrom identification. Drug Metab Dispos 312:345–350, 2003

    Google Scholar 

  27. Brandon EFA, Raap CD, Meijerman I, Beijnen JH, Schellens JHM: An update on in vitro test methods in human hepatic drug biotransformation research: Pros and cons. Toxicol Appl Pharmacol 189:233–246, 2003

    Article  CAS  PubMed  Google Scholar 

  28. Lin JH: Sense and nonsense in the prediction of drug-drug interactions. Curr Drug Metab 1:305–331, 2000

    Article  CAS  PubMed  Google Scholar 

  29. Bachman KA, Ghosh R: The use of in vitro methods to predict in vivo pharmacokinetics and drug interactions. Current Drug Metabolism 2:299–314, 2001

    Google Scholar 

  30. Lin JH, Lu AYH: Inhibition and induction of cytochrome P450 and the clinical implications. Clin Pharmacokinet 35:361–390, 1998

    Article  CAS  PubMed  Google Scholar 

  31. Dahl ML: Cytochrome P450 phenotyping/genotyping in patients receiving antipsychotics: Useful aid to prescribing? Clin Pharmacokinet 41:453–470, 2002

    Article  CAS  PubMed  Google Scholar 

  32. Tucker GT: The rationel selection of drug interaction studies: Implication of recent advantages in drug metabolism. Int J Clin Pharmacol Ther Toxicol 30:550–553, 1992

    CAS  PubMed  Google Scholar 

  33. Levy RH, Thummel KE, Trager WF, Hansten PD, Eichelbaum M: Metabolic drug intractions. Lippincott Williams and Wilkins, Philidelphia, 2000

    Google Scholar 

  34. Desai PB, Duan JZ, Zhu YW, Kouzi S: Human liver microsomal metabolism of paclitaxel and drug interactions. Eur J Drug Metab Pharmacokinet 23:417–424, 1998

    CAS  PubMed  Google Scholar 

  35. Laverdiere C, Kolb EA, Supko GJ, Gorlick R, Meyers PA, Maki RG, Wexler L, Demetri GD, Healey JH, Huvor AG, Goorin AM, Bagatell R, Ruiz-Casado A, Guzman C, Jimeno J, Harmon D. Phase II study of Ecteinascidin 743 in heavily pretreated patients with recurrent osteosarcoma. Cancer 98:832–840, 2003

    Article  CAS  PubMed  Google Scholar 

  36. Donald S, Verschoyle RD, Greaves P, Colombo T, Zucchetti M, Falcioni C, Zaffaroni M, D'Incalci M, Manson MM, Jimeno J, Steward WP, Gescher AJ: Dietary agent indole-3-carbinol protects female rats against the hepatotoxicity of the antitumor drug ET-743 (trabectidin) without compromising efficacy in a rat mammary carcinoma. Int. J. Cancer 111:961–967, 2004

    Article  CAS  PubMed  Google Scholar 

  37. Donald S, Verschoyle RD, Greaves P, Orr S, Jimeno J, Gescher AJ: Comparison of four modulators of drug metabolism as protectants against the hepatotoxicity of the novel antitumor drug yondelis (ET-743) in the female rat and in hepatocytes in vitro. Cancer Chemother. Pharmacol. 53:305–312, 2004

    Article  CAS  PubMed  Google Scholar 

  38. D'Incalci MD, Jimeno J: Preclinical and clinical results with the natural marine product ET-743. Exp. Opinion Invest Drugs 12:1843–1853, 2003

    Google Scholar 

  39. Tanaka E: Gender-related differences in pharmacokinetics and their clinical significance. J Clin Pharm Ther 24:339–346, 1999

    CAS  PubMed  Google Scholar 

  40. Wormhoudt LW, Commandeur JNM, Vermeulen NPE: Genetic polymorphisms of human N-acetyltransferase, cytochrome P450, glutathione-S-transferase, and epoxide hydrolase enzymes: Relevance to xenobiotic metabolism and toxicity. Crit Rev Toxicol 29:59–124, 1999

    Article  CAS  PubMed  Google Scholar 

  41. Eiselt R, Domanski TL, Zibat A, Mueller R, Presecan-Siedel E, Hustert E, Zanger UM, Brockmoller J, Klenk HP, Meyer UA, Khan KK, He YA, Halpert JR, Wojnowski L: Identification and functional characterization of eight CYP3A4 protein variants. Pharmacogenetics 11:447–458, 2001

    Article  CAS  PubMed  Google Scholar 

  42. van Schaik RH, van der Heiden IP, van den Anker JN, Lindemans J: CYP3A5 variant allele frequencies in Dutch Caucasians. Clin Chem 48:1668–1671, 2001

    Google Scholar 

  43. MacKenzie PI, Miners JO, McKinnon RA: Polymorphisms in UDP glucuronosyltransferase genes: Functional consequences and clincial relevance. Clin Chem Lab Med 38:889–892, 2000

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Rolf W. Sparidans PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brandon, E.F.A., Sparidans, R.W., Guijt, KJ. et al. In vitro characterization of the human biotransformation and CYP reaction phenotype of ET-743 (Yondelis®, Trabectidin®), a novel marine anti-cancer drug. Invest New Drugs 24, 3–14 (2006). https://doi.org/10.1007/s10637-005-4538-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-005-4538-9

Keywords

Navigation