Published in:
01-04-2010 | PRECLINICAL STUDIES
Disposition and toxicity of trabectedin (ET-743) in wild-type and mdr1 gene (P-gp) knock-out mice
Authors:
J. H. Beumer, N. E. Franke, R. Tolboom, T. Buckle, H. Rosing, L. Lopez-Lazaro, J. H. M. Schellens, J. H. Beijnen, O. van Tellingen
Published in:
Investigational New Drugs
|
Issue 2/2010
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Summary
Trabectedin is a novel anticancer drug active against soft tissue sarcomas. Trabectedin is a substrate for P-glycoprotein (P-gp), which is encoded by mdr1a/1b in rodents. Plasma and tissue distribution, and excretion of [14C]-trabectedin were evaluated in wild-type and mdr1a/1b(−/−) mice. In parallel, we investigated the toxicity profile of trabectedin by serial measurements of blood liver enzymes and general pathology. [14C]-trabectedin 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 P-gp was absent, but organs under wild type circumstances protected by P-gp showed increased trabectedin concentrations in mdr1a/1b(−/−) mice. Although hepatic trabectedin concentrations were not increased when P-gp was absent, mdr1a/1b(−/−) mice experienced more severe liver toxicity. P-gp plays a role in the in vivo disposition and toxicology of trabectedin.