title: In vitro characterization of the human biotransformation and CYP reaction phenotype of ET-743 (Yondelis, Trabectidin), a novel marine anti-cancer drug.
abstract: 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.
authors.affiliation: Faculty of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Esther F A
authors.initials: EF
authors.lastname: Brandon
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Sparidans
authors.forename: Kees-Jan
authors.initials: KJ
authors.lastname: Guijt
authors.forename: Sjoerd
authors.initials: S
authors.lastname: Löwenthal
authors.forename: Irma
authors.initials: I
authors.lastname: Meijerman
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics*; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004149:Dioxoles / Q000493:pharmacokinetics*; D005260:Female; D014453:Glucuronosyltransferase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000493:pharmacokinetics*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010641:Phenotype; D012737:Sex Factors; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; C472000:UDP-glucuronosyltransferase 2B15, human; D005982:Glutathione Transferase; D000077606:Trabectedin