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

3区 · 医学

Article

作者: Gabriele Fontana ; Maurizio D’Incalci ; Cristiano Falcioni ; Elena Marangon ; Massimo Zucchetti ; Carla Manzotti

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%).

2005-08-01·Tetrahedron

Selective synthesis of 14β-amino taxanes

作者: Gabriele Fontana ; Eleonora Baldelli ; Donato Pocar ; Giacomo Carenzi ; Ezio Bombardelli ; Maria Luisa Gelmi ; Andrea Guerrini ; Arturo Battaglia

The base induced deprotonation of H-14 of 7-triethylsilyl- (7-TES-) and 7-tert-butoxycarbonyl- (7-BOC-) protected 13-oxo-baccatins gave the corresponding enolates, which were selectively aminated with electrophilic nitrogen donors, such as azodicarboxylates and tosyl azide.In particular, tosyl azide gave the corresponding 7-BOC- and 7-TES-13-oxo-14β-azido-baccatin III.Alternatively, the last compound was prepared via NaN₃ induced azidation of the 13-silyl enol ether of 7-TES-13-oxo-baccatin III under oxidative (cerium ammonium nitrate) conditions.The 13-silyl enol ether was obtained in a multistep process by DBU induced silylation of 7-TES-13-oxo-baccatin III.7-TES-13-oxo-14β-azido-baccatin III (I) was used as a key intermediate for the synthesis of a new family of antitumor taxanes containing amino based functional groups at the C-14 position, such as: 14β-azido, 14β-amino, 14β-amino 1,14-carbamate, 14β-amino 1,14-thiocarbamate, and 14β-amino N-tert-butoxycarbonyl-1,14-carbamate.

100 项与 IDN 5738 相关的药物交易

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