title: Development and validation of a LC-MS/MS method for the determination of the novel oral 1,14 substituted taxane derivatives, IDN 5738 and IDN 5839, in mouse plasma and its application to the pharmacokinetic study.
abstract: Two LC-ESI-MS and CID-MS/MS methods were developed and validated for pharmacokinetic studies of the novel oral taxane derivatives IDN 5738 and IDN 5839, used for preclinical evaluation in mice. The analysis requires 100muL of plasma sample, involves the addition of an internal standard and protein precipitation with 0.1% HCOOH in acetonitrile. The HPLC separation was obtained on Sunfire C18 column and Selected Reaction Monitoring technique was used to quantify the taxanes. The recoveries were more than 90%; the methods were linear over the validated concentrations range of 25-1500ng/mL for IDN 5738 and 25-5000ng/mL for IDN 5839 and had a limit of detection of 0.14 and 0.25ng/mL, respectively. The inter-day coefficient of variation (CV%) of the calibration standards ranged between 1.3 and 7.2% for IDN 5738 and between 0.0 and 9.0% for IDN 5839 and the mean accuracy was in the range 85.3-112.0% for IDN 5738 and between 80.0 and 111.0% for IDN 5839. Moreover, analysing quality control plasma samples on three different days, the methods resulted precise and accurate showing intra- and inter-day CV within 12% for both analytes, and accuracy of 92.0-113.3% and 85.9-105.7% for IDN 5738 and IDN 5839, respectively. With these methods, we studied for the first time, the pharmacokinetics of the two taxanes showing for both, good oral bioavailability (>50%).
authors.affiliation: Laboratory of Cancer Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156 Milan, Italy. marangon@marionegri.it
authors.forename: Elena
authors.initials: E
authors.lastname: Marangon
authors.forename: Cristiano
authors.initials: C
authors.lastname: Falcioni
authors.forename: Carla
authors.initials: C
authors.lastname: Manzotti
authors.forename: Gabriele
authors.initials: G
authors.lastname: Fontana
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
authors.forename: Massimo
authors.initials: M
authors.lastname: Zucchetti
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood*; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D005260:Female; D057230:Limit of Detection; D051379:Mice; D015394:Molecular Structure; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D053719:Tandem Mass Spectrometry / Q000379:methods*; D043823:Taxoids / Q000097:blood* / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D043823:Taxoids