title: Determination of aplidin, a marine-derived anticancer drug, in human plasma, whole blood and urine by liquid chromatography with electrospray ionisation tandem mass spectrometric detection.
abstract: A sensitive and highly specific liquid chromatographic method with electrospray ionisation tandem mass spectrometric detection (LC-ESI-MS/MS) is reported for the determination in human plasma, whole blood and urine of Aplidin (APL), a novel depsipeptide derived from the tunicate Aplidium albicans with a potent cytotoxic activity under investigation in clinical studies. Didemnin B was used as internal standard and, after protein precipitation with acetonitrile and liquid-liquid extraction with chloroform, APL was separated by liquid chromatography using a reversed-phase C18 column and a linear gradient of acetonitrile in water (both containing 0.5% formic acid). Detection was performed using a turboionspray source operated in positive ion mode and by multiple reaction monitoring (MRM; m/z 1111 --> 295 for APL and m/z 1113 --> 297 for didemnin B). The method was linear (r > or = 0.9933) over the range 1-250 ng/ml, with intra- and inter-batch precision and accuracy below 12.2% (except at LLOQ < or = 15.4%) for both plasma and urine. Recoveries were moderate, ranging from 54 to 70% in plasma and blood, and from 46 to 60% in urine, for both APL and didemnin B. The LOD was 0.25 ng/ml for both matrices. APL resulted stable in the different matrices at least for 6 h (both at room temperature and 37 degrees C), after freeze and thaw cycles and long term storage at -20 degrees C. The method allowed demonstrating that APL is in a dynamic equilibrium between plasma and blood cells. Moreover, the method was successfully applied to the pharmacokinetic study of Aplidin in cancer patients.
authors.affiliation: Istituto di Ricerche Farmacologiche Mario Negri, G. Paone Environmental Health Center, Consorzio Mario Negri Sud, Via Nacional, 66030 Santa Maria Imbaro, Chieti, Italy. celli@negrisud.it
authors.forename: Nicola
authors.initials: N
authors.lastname: Celli
authors.forename: Barbara
authors.initials: B
authors.lastname: Mariani
authors.forename: Francesco
authors.initials: F
authors.lastname: Di Carlo
authors.forename: Massimo
authors.initials: M
authors.lastname: Zucchetti
authors.forename: Luis
authors.initials: L
authors.lastname: Lopez-Lazaro
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
authors.forename: Domenico
authors.initials: D
authors.lastname: Rotilio
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000032:analysis* / Q000097:blood / Q000652:urine; D002853:Chromatography, Liquid / Q000379:methods; D047630:Depsipeptides; D006801:Humans; D010456:Peptides, Cyclic / Q000032:analysis* / Q000097:blood / Q000652:urine; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*; D014561:Urochordata
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; D010456:Peptides, Cyclic; C098980:plitidepsin