title: Disposition and toxicity of trabectedin (ET-743) in wild-type and mdr1 gene (P-gp) knock-out mice.
abstract: 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 [(14)C]-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. [(14)C]-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.
authors.affiliation: Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Louwesweg 6, 1066 EC Amsterdam, The Netherlands. beumerjh@upmc.edu
authors.forename: J H
authors.initials: JH
authors.lastname: Beumer
authors.forename: N E
authors.initials: NE
authors.lastname: Franke
authors.forename: R
authors.initials: R
authors.lastname: Tolboom
authors.forename: T
authors.initials: T
authors.lastname: Buckle
authors.forename: H
authors.initials: H
authors.lastname: Rosing
authors.forename: L
authors.initials: L
authors.lastname: Lopez-Lazaro
authors.forename: J H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: O
authors.initials: O
authors.lastname: van Tellingen
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency* / Q000235:genetics*; D000818:Animals; D019540:Area Under Curve; D004149:Dioxoles / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D018345:Mice, Knockout; D044005:Tetrahydroisoquinolines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity*; D014018:Tissue Distribution / Q000187:drug effects; D000077606:Trabectedin
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004149:Dioxoles; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin