Investigational New Drugs

, Volume 24, Issue 1, pp 3–14

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

  • Esther F. A. Brandon
  • Rolf W. Sparidans
  • Kees-Jan Guijt
  • Sjoerd Löwenthal
  • Irma Meijerman
  • Jos H. Beijnen
  • Jan H. M. Schellens
Article

DOI: 10.1007/s10637-005-4538-9

Cite this article as:
Brandon, E.F.A., Sparidans, R.W., Guijt, KJ. et al. Invest New Drugs (2006) 24: 3. doi:10.1007/s10637-005-4538-9

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 Km 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.

Keywords

ET-743biotransformationcytochrome P450 (CYP)conjugationCYP reaction phenotype

Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  • Esther F. A. Brandon
    • 1
  • Rolf W. Sparidans
    • 1
    • 4
  • Kees-Jan Guijt
    • 1
  • Sjoerd Löwenthal
    • 1
  • Irma Meijerman
    • 1
  • Jos H. Beijnen
    • 1
    • 2
  • Jan H. M. Schellens
    • 1
    • 3
  1. 1.Faculty of Pharmaceutical SciencesUtrecht UniversityUtrechtThe Netherlands
  2. 2.Slotervaart HospitalAmsterdamThe Netherlands
  3. 3.The Netherlands Cancer InstituteAmsterdamThe Netherlands
  4. 4.Pharmaceutical Sciences-Biomedical Analysis—Drug ToxicologyUtrecht UniversityUtrechtThe Netherlands