Disposition and toxicity of trabectedin ET743 i

Authors: J H Beumer N E Franke R Tolboom T Buckle H Rosing L LopezLazaro J H M Schellens J H Beijnen O van Tellingen

Publish Date: 2009/02/24

Volume: 28, Issue: 2, Pages: 145-155

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Abstract

Trabectedin is a novel anticancer drug active against soft tissue sarcomas Trabectedin is a substrate for Pglycoprotein Pgp which is encoded by mdr1a/1b in rodents Plasma and tissue distribution and excretion of 14Ctrabectedin were evaluated in wildtype and mdr1a/1b−/− mice In parallel we investigated the toxicity profile of trabectedin by serial measurements of blood liver enzymes and general pathology 14Ctrabectedin was extensively distributed into tissues and rapidly converted into a range of unknown metabolic products The excretion of radioactivity was similar in both genotypes The plasma clearance of unchanged trabectedin was not reduced when Pgp was absent but organs under wild type circumstances protected by Pgp showed increased trabectedin concentrations in mdr1a/1b−/− mice Although hepatic trabectedin concentrations were not increased when Pgp was absent mdr1a/1b−/− mice experienced more severe liver toxicity Pgp plays a role in the in vivo disposition and toxicology of trabectedinThe authors gratefully acknowledge the statistical assistance of Guus Hart and the biotechnical assistance of Ton Schrauwers and Martin van der Valk for providing expert pathology reports We also thank the University of Pittsburgh Cancer Institute Hematology/Oncology Writing Group for constructive suggestions regarding the manuscriptThis work was paid for by PharmaMar Colmenar Viejo Madrid Spain The study sponsor had a chance to make recommendations to the investigatorinitiated study proposal The sponsor had no input in data collection analysis and interpretation but did have input in the reviewing of the report

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