Search for metabolites of ecteinascidin 743, a novel, marine-derived, anti-cancer agent, in man

Ecteinascidin 743 (ET-743) is a potent anti-tumoral agent of a marine origin. It is currently being tested in phase II clinical trials using a 3-weekly 24-h i.v. infusion of 1500 μg/m² and 3-h infusions of 1650 μg/m². Knowledge of the metabolism of ET-743 is, however, still scarce. In the present study, a qualitative chromatographic discovery of metabolites of ET-743 in man is reported. ET-743 and its demethylated analog ET-729 were incubated at 37°C in the presence of enzyme systems, pooled human microsomes, pooled human plasma and uridine 5′-diphosphoglucuronyltransferase, respectively, in appropriate media. Reaction products were investigated chromatographically using photodiode array and ion spraymass spectrometric detection (LC-MS). The main reaction products in microsomal incubations of ET-743 resulted from a remarkable breakdown of the molecule. In plasma the drugs were deacetylated, and the transferase did actually yield a glucuronide of both ET-743 and ET-729. In contrast, screening of urine, plasma and bile, collected from patients treated with ET-743 at the highest dose levels, using a sensitive LC-MS assay, did not result in detection of ET-729 and metabolites which were generated in vitro. The urinary excretion of ET-743 in man was lower than 0.7% of the administered dose for a 24-h infusion.