A rapid and sensitive HPLC-MS/MS method for determination of an aminopyridazine derived anti-neuroinflammatory agent (ZW14) in dog plasma: Application to a pharmacokinetic study

摘要

The unclear etiology of Alzheimer's disease leaves a large space for drug exploration. A novel antineuroinfiammation agent (ZW14) was previously determined to have comparable efficacy to the marketed drug (donepezil) in the A beta-induced model mice. Herein, a sensitive and rapid HPLC MS/MS quantitative method was developed and validated for the further evaluation of ZW14 in dogs. Plasma samples were processed by liquid liquid extraction with ethyl acetate and separated on Luna C18 column (2.1 mm x 50 min, 1.711 mu m) at room temperature with a flow rate of 0.2 mL/min. The analyte and IS were all detected by monitoring the precursor product ion transition at unit resolution using multiple reaction monitoring (MRM) scan mode with positive ionization mode. No endogenous interference was observed and the linear range was 0.05-1500 ng/mL with the lower limit of quantification of 0.05 ng/mL. The intra- and inter-day precisions were within 10.9%, while the accuracy was all between 96.0% and 110%. The developed method was successfully applied to the pharmacoldnetic study of ZW14 in beagle dogs after oral and intravenous administration of 2 mg/kg. The oral bioavailability of ZW14 was 26.3% with half-life of 2.6 h. (C) 2015 Elsevier B.V. All rights reserved.