PMID: 11604552Oct 18, 2001Paper

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

Anti-cancer Drugs
Rolf W SparidansJos H Beijnen

Abstract

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 microg/m(2) and 3-h infusions of 1650 microg/m(2). 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 degrees 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 spray-mass 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 ...Continue Reading

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Citations

Sep 22, 2006·Cancer Chemotherapy and Pharmacology·Jan H BeumerJos H Beijnen
Sep 1, 2005·Investigational New Drugs·J H BeumerJ H M Schellens
Feb 25, 2009·Investigational New Drugs·J H BeumerO van Tellingen
Mar 8, 2005·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·J H BeumerJ H Beijnen
Jun 6, 2009·Expert Review of Anticancer Therapy·Laurence BoudouPhilippe A Cassier
Sep 10, 2003·Anti-cancer Drugs·Ch van KesterenJ H Beijnen

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