title: Evaluation of human plasma protein binding of trabectedin (Yondelis, ET-743).
abstract: Trabectedin (ET-743, Yondelis) is a novel anticancer drug with impressive activity in soft tissue sarcoma with a manageable, non-cumulative toxicity profile. Protein binding can be a major determinant of unbound concentration, volume of distribution, renal and hepatic clearance, and the half-life of a drug. Human plasma protein binding of trabectedin has not previously been reported. Using ultrafiltration techniques, we determined the human plasma protein binding of trabectedin at a clinically relevant concentration. Experiments with a panel of co-medications representing all known protein-binding sites showed that the concentration of unbound trabectedin could be increased by high concentrations of phenytoin. The other tested co-medications, at concentrations covering their respective therapeutic ranges, did not displace trabectedin from its plasma protein binding. This suggests that trabectedin binds to albumin site I (total protein binding of 94.2 +/-0.6 %) displaying an association constant of 2.6 +/-0.2 10(4) M(-1). Because trabectedin is an intermediate-to-high hepatic extraction drug, changes in unbound fraction will not have a major impact on elimination processes. The high protein binding may have implications for the interpretation of in vitro data, which are usually performed in the presence of low protein levels. We can conclude that the studied co-medications are unlikely to have clinically relevant effects on trabectedin binding to plasma proteins at therapeutic concentrations.
authors.affiliation: Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands. beumerjh@upmc.edu
authors.forename: Jan Handrick
authors.initials: JH
authors.lastname: Beumer
authors.forename: L
authors.initials: L
authors.lastname: Lopez-Lazaro
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Olaf
authors.initials: O
authors.lastname: van Tellingen
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry / Q000378:metabolism*; D001798:Blood Proteins / Q000378:metabolism*; D004149:Dioxoles / Q000737:chemistry / Q000378:metabolism*; D004347:Drug Interactions; D006801:Humans; D066298:In Vitro Techniques; D010672:Phenytoin / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D044005:Tetrahydroisoquinolines / Q000737:chemistry / Q000378:metabolism*; D000077606:Trabectedin; D014462:Ultrafiltration
chemical_list: D018906:Antineoplastic Agents, Alkylating; D001798:Blood Proteins; D004149:Dioxoles; D044005:Tetrahydroisoquinolines; D010672:Phenytoin; D000077606:Trabectedin