Simple and sensitive LC-MS/MS method for simultaneous determination of crizotinib and its major oxidative metabolite in human plasma: Application to a clinical pharmacokinetic study.
In this study, a fast, simple and sensitive liquid chromatography-mass spectrometry method was developed for simultaneous determination of crizotinib and its major oxidative metabolite crizotinib-lactam in human plasma. The plasma samples were deproteinated by using acetonitrile containing 0.1% formic acid as precipitant whereas the chromatographic separation was obtained on a C18 column with 0.1% formic acid aqueous and acetonitrile/methanol (v:v, 1:1) as mobile phase. The mass detector was operated in positive selected reaction monitoring mode. Precursor-to-product transitions were optimized to be m/z 450.1/260.1, m/z 464.1/98.1, and m/z 326.1/291.1 for crizotinib, crizotinib-lactam and midazolam (internal standard), respectively. The established method was validated in accordance with guidance issued by Food and Drug Administration. The assay showed good linearity over the concentration ranges of 0.1-1000 ng/mL for crizotinib and 0.1-400 ng/mL for crizotinib-lactam, with correlation coefficients more than 0.999 (r > 0.999). The extraction recovery was more than 87.12%. No significant matrix effect and carryover were observed. The precision (RSD, %) was less than 8.27%, whereas accuracy (RE, %) was within the range of -4.56 to 7.08%. The validated method has been successfully applied to the clinical pharmacokinetic study of crizotinib and crizotinib-lactam in human plasma after oral administration of crizotinib at a single dose of 250 mg. The results revealed that crizotinib was rapidly metabolized into its metabolite crizotinib-lactam and the in vivo exposure of crizotinib-lactam was 38.50% of that of crizotinib.
['Qi|Xiaoyan|X|', 'Zhao|Lin|L|', 'Zhao|Qiuping|Q|', 'Xu|Qiaoxia|Q|']
D000284:Administration, Oral D000328:Adult D002853:Chromatography, Liquid D000077547:Crizotinib D006801:Humans D008297:Male D008875:Middle Aged D010949:Plasma D011720:Pyrazoles D011725:Pyridines D015203:Reproducibility of Results D053719:Tandem Mass Spectrometry
Crizotinib Oxidative metabolite Human Pharmacokinetics