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 origi n. It is currently being tested in phase II clinical trials using a 3-weekl y 24-h ix. infusion of 1500 mug/m(2) and 3-h infusions of 1650 mug/m(2). Kn owledge of the metabolism of ET-743 is, however, still scarce. In the prese nt study, a qualitative chromatographic discovery of metabolites of ET-743 in man is reported. ET-743 and its demethylated analog ET-729 were incubate d at 37 degreesC in the presence of enzyme systems, pooled human microsomes , pooled human plasma and uridine 5'-diphosphoglucuronyltransferase, respec tively, in appropriate media. Reaction products were investigated chromatog raphically using photodiode array and ion spray-mass spectrometric detectio n (LC-MS). The main reaction products in microsomal incubations of ET-743 r esulted from a remarkable breakdown of the molecule. In plasma the drugs we re deacetylated, and the transferase did actually yield a glucuronide of bo th ET-743 and ET-729. In contrast, screening of urine, plasma and bile, col lected 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 metaboli tes which were generated in vitro. The urinary excretion of ET-743 in man w as lower than 0.7% of the administered dose for a 24-h infusion. [(C) 2001 Lippincott Williams & Wilkins.].