Quantification of sunitinib in mouse plasma, brain tumor and normal brain using liquid chromatography-electrospray ionization-tandem mass spectrometry and pharmacokinetic application

The primary challenge associated with the development of an assay method for the determination of drug concentrations in relatively small amount of mouse plasma and tissue samples is to improve extraction efficiency and detection sensitivity. In this work, a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based method combined with protein precipitation, liquid-liquid extraction and solid-phase extraction techniques was developed for the determination of sunitinib in mouse plasma, brain tumor and normal brain tissue, respectively. The instrument was operated under the multiple reaction monitoring (MRM) mode using electrospray ionization (ESI) in the positive ion mode. A good linear relationship with coefficients of determination >= 0.99 was achieved over the concentration ranges of 1.37-1000 ng/mL for plasma and 4.12-1000 ng/g for the normal brain and brain tumor. The limits of quantification (LOQs) for sunitinib in mouse plasma, brain tumor and normal brain tissue are 1.37 ng/mL, 4.12 ng/g and 4.12 ng/g, respectively. The reproducibility of the LC-MS/MS method is reliable, with the intra- and inter-day precision being less than 15% and accuracy within +/- 15%. The established method was successfully applied to the characterization of sunitinib disposition in the brain and brain tumor as well as its systemic pharmacokinetics in a murine orthotopic glioma model. (C) 2009 Elsevier B.V. All rights reserved.