Search for metabolites of ecteinascidin 743, a novel, marine-derived, anti-cancer agent, in man
Sparidans, R.W.; Rosing, H.; Hillebrand, M.J.X.; López-Lázaro, L.; Jimeno, J.M.; Manzanares, I.; van Kesteren, C.; Cvitkovic, E.; van Oosterom, A.T.; Schellens, J.H.M.; Beijnen, J.H. (2001). Search for metabolites of ecteinascidin 743, a novel, marine-derived, anti-cancer agent, in man. Anti-Cancer Drugs 12(8): 653-666. https://hdl.handle.net/10.1097/00001813-200109000-00003
In: Anti-Cancer Drugs. Lippincott Williams & Wilkins: Philadelphia. ISSN 0959-4973; e-ISSN 1473-5741, more
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| Keyword |
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| Author keywords |
ecteinascidin 729; ecteinascidin 743; high-performance liquid chromatography; metabolism; microsomes |
| Authors | | Top |
- Sparidans, R.W.
- Rosing, H.
- Hillebrand, M.J.X.
- López-Lázaro, L.
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- Jimeno, J.M.
- Manzanares, I.
- van Kesteren, C.
- Cvitkovic, E.
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- van Oosterom, A.T., more
- Schellens, J.H.M.
- Beijnen, J.H.
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| 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 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 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 urinary excretion of ET-743 in man was lower than 0.7% of the administered dose for a 24-h infusion. |
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