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

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.