Liquid chromatography-tandem mass spectrometric assay for the ALK inhibitor crizotinib in mouse plasma

by ScienceDirect Publication: Journal of Chromatography B on August 21, 2012

Publication year: 2012
Source:Journal of Chromatography B

Rolf W. Sparidans, Seng Chuan Tang, Luan N. Nguyen, Alfred H. Schinkel, Jan H.M. Schellens, Jos H. Beijnen

A quantitative bioanalytical liquid chromatography-tandem mass spectrometric (LC-MS/MS) assay for the ALK inhibitor crizotinib was developed and validated. Plasma samples were pre-treated using protein precipitation with acetonitrile containing crizotinib-13C2-2H5 as internal standard. The extract was directly injected into the chromatographic system after dilution with water. This system consisted of a sub-2μm particle, trifunctional bonded octadecyl silica column with a gradient using 0.1% (v/v) of ammonium hydroxide in water and methanol. The eluate was transferred into the electrospray interface with positive ionization and the analyte was detected in the selected reaction monitoring mode of a triple quadrupole mass spectrometer. The assay was validated in a 10-10,000ng/ml calibration range with r2 =0.99980±0.00014 for double logarithmic linear regression (n =5). Within day precisions (n =6) were 3.4-4.8%, between day (3 days; n =18) precisions 3.6-4.9%. Accuracies were between 107-112% for the whole calibration range. The drug was sufficiently stable under all relevant analytical conditions. Oxidative metabolites of crizotinib were monitored semi-quantitatively. Finally, the assay was successfully used to assess drug pharmacokinetics in mice.

Highlights

► The first validated bioanalytical assay for crizotinib has been reported. ► The assay has successfully been validated in the 10-10,000ng/ml range. ► The drug is stable under all conditions relevant for the assay. ► Oxidative metabolites can simultaneously be monitored. ► First pharmacokinetics in male wild type FVB mice have reported.



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