TY - JOUR
T1 - Search for metabolites of ecteinascidin 743, a novel, marine-derived, anti-cancer agent, in man
AU - Sparidans, Rolf W.
AU - Rosing, Hilde
AU - Hillebrand, Michel J X
AU - López-Lázaro, Luis
AU - Jimeno, José M.
AU - Manzanares, Ignacio
AU - Van Kesteren, Charlotte
AU - Cvitkovic, Esteban
AU - Van Oosterom, Alan T.
AU - Schellens, Jan H M
AU - Beijnen, Jos H.
PY - 2001
Y1 - 2001
N2 - 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.
AB - 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.
KW - Ecteinascidin 729
KW - Ecteinascidin 743
KW - High-performance liquid chromatography
KW - Metabolism
KW - Microsomes
UR - http://www.scopus.com/inward/record.url?scp=17944372337&partnerID=8YFLogxK
U2 - 10.1097/00001813-200109000-00003
DO - 10.1097/00001813-200109000-00003
M3 - Article
C2 - 11604552
AN - SCOPUS:17944372337
SN - 0959-4973
VL - 12
SP - 653
EP - 666
JO - Anti-Cancer Drugs
JF - Anti-Cancer Drugs
IS - 8
ER -