Determination of larotaxel and its metabolites in rat plasma by liquid chromatography-tandem mass spectrometry: Application for a pharmacokinetic study

摘要

A sensitive and reliable high-performance liquid chromatography-mass spectrometry (LC-MS/MS) method was developed and validated for determination of larotaxel (LTX) and its active metabolites (M1, M2 and M3) in rat plasma. The analytes were extracted by one-step protein precipitation and separated on a Capcell pak C_(18) column (2.0 mm×100 mm; 2 μm; Shiseido) using methanol-water as mobile phase at a flow rate of 0.2 mL min~(-1) in gradient mode. The method was validated over the concentration range of 2.5-1250 ng mL~(-1) for LTX and 1.0-500 ng mL~(-1) for M1, respectively, while M2 and M3 were monitored semi-quantitatively and quantified as M1 equivalents. Intra- and inter-day accuracy and precision were within the acceptable limits of less than 15% at all concentrations. Coefficients of correlation (r) for the calibration curves were more than 0.99 for all analytes. The quantitation method was successfully applied for simultaneous estimation of LTX and its metabolites in a pharmacokinetic study after oral administration at different doses of 10, 20, and 40mg/kg and intravenous administration at the dose 10mg/kg to Wistar rats, respectively. The results indicated that larotaxel has linear pharmacokinetic characteristics in rats after oral administration and its absolute bioavailability in rats was 12.24%.