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

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

来源：Journal of Chromatography B-Analytical Technologies in the Biomedical and Life Sciences, 2009, 877(32): 4147-4153.

DOI：10.1016/j.jchromb.2009.10.016

• LC-ESI-MS and CID-MS/MS method development
• SRM analysis
• Oral taxanes
• Preclinical pharmacokinetics

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 100 mu L 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 25-1500 ng/mL for IDN 5738 and 25-5000 ng/mL for IDN 5839 and had a limit of detection of 0.14 and 0.25 ng/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%).

• 出版日期2009-12-15