In-vitro cytotoxicity of ET-743 (Trabectedin, Yondelis), a marine anti-cancer drug, in the Hep G2 cell line: influence of cytochrome P450 and phase II inhibition, and cytochrome P450 induction.

Article Details

Citation

Brandon EF, Meijerman I, Klijn JS, den Arend D, Sparidans RW, Lazaro LL, Beijnen JH, Schellens JH

In-vitro cytotoxicity of ET-743 (Trabectedin, Yondelis), a marine anti-cancer drug, in the Hep G2 cell line: influence of cytochrome P450 and phase II inhibition, and cytochrome P450 induction.

Anticancer Drugs. 2005 Oct;16(9):935-43.

PubMed ID
16162970 [ View in PubMed
]
Abstract

ET-743 is a marine anti-cancer drug and is currently in phase I trials in which the effect of combination therapies will be investigated. Its dose-limiting toxicity in patients is hepatotoxicity. In-vitro studies have shown that ET-743 is mainly metabolized by cytochrome P450 (CYP) 3A4, but also by 2C9, 2C19, 2D6 and 2E1, and the phase II enzymes uridine diphosphoglucuronosyl transferase and glutathione-S-transferase. Based on this metabolic profile, there is a risk of drug-drug interactions possibly influencing the hepatotoxicity of ET-743. Therefore, the effect of CYP and phase II activity on the cytotoxicity of ET-743 was investigated in vitro in a human cell line model system. The effect of different CYP and phase II inhibitors and CYP inducers on ET-743 cytotoxicity was studied after 48 and 120 h of treatment in Hep G2 cells using different assays. Furthermore, the toxicity of ET-743 metabolites was investigated. Potent cytotoxic activity of ET-743 after 120 h treatment was observed, which could be increased in combination with the CYP inhibitors metyrapone (3A4), phenanthrene (substrate for 2E1, 3A4), piperonyl butoxide (3A), proadifen (2C9, 2E1, 3A4), ritonavir (3A4), and warfarin (2C9, 2C19). No effect on the cytotoxicity of ET-743 was observed in combination with phase II enzyme inhibition and CYP induction. CYP metabolites of ET-743 were less toxic compared with ET-743. These findings indicate that combination therapy of ET-743 with CYP inhibitors, e.g. other anti-cancer drugs, could lead to changes in the hepatotoxicity of ET-743 and are therefore of clinical importance.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
MetyraponeCytochrome P450 3A4ProteinHumans
Unknown
Inhibitor
Inducer
Details
TrabectedinCytochrome P450 2C9ProteinHumans
Unknown
Substrate
Details
TrabectedinCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Details
WarfarinCytochrome P450 2C19ProteinHumans
Unknown
Substrate
Inhibitor
Details
Drug Interactions
DrugsInteraction
Acenocoumarol
Amitriptyline
The therapeutic efficacy of Acenocoumarol can be decreased when used in combination with Amitriptyline.
Warfarin
Amitriptyline
The therapeutic efficacy of Warfarin can be decreased when used in combination with Amitriptyline.