Simultaneous determination of paclitaxel and lansoprazole in rat plasma by LC-MS/MS method and its application to a preclinical pharmacokinetic study of investigational PTX-LAN-PLGA nanoformulation

摘要

In spite of having a remarkable anti tumor activity against a wide variety of cancers, the clinical effectiveness of the major chemotherapeutic drug paclitaxel is often limited by the issues of drug resistance that hampers the therapeutic effectiveness of the drug. The combination of proton pump inhibitor with paclitaxel is an effective approach to overcome therapeutic resistance caused by the acidic microenvironment (Warburg effect) in tumor. In the present study a new simple, precise and selective liquid chromatography tandem mass spectrometry method was developed for quantification of paclitaxel and lansoprazole using esomeprazole as an internal standard and applied for the pharmacokinetic study of investigational paclitaxel - lansoprazole loaded PLGA nanoparticles. The developed method quantifies both the drugs simultaneously irrespective of their dissimilar stability concerns. The detection was exercised with multiple reaction-monitoring mode in positive ionization that yielded highly intense response of parent-product (m/z) transition pair 854.4 -> 286.1, 370.1 -> 251.9 and 346 -> 198 for paclitaxel, lansoprazole and Esomeprazole respectively. The chromatographic separation was achieved using phenomenex Kinetex 5 mu C18 100A 50 x 3.0 mm column and a gradient mobile phase combination of ammonium acetate in deionized water (pH 6.8, 2 mM, w/v) and acetonitrile spiked with formic acid (1:1000, v/v ). This method showed good linearity over a concentration range of 10-320 ng/mL and 100-3200 ng/mL with correlation coefficient (R-2) 0.98 and 0.94 for paclitaxel and lansoprazole respectively. Using liquid liquid extraction process both the drugs were extracted from rat plasma. The intra- and inter-day precision and accuracy values were within the variability limits and both the analytes were found to be stable throughout the freeze-thaw, auto-sampler, bench top and long term stability studies. The liquid chromatography tandem mass spectrometry method was successfully v