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Simultaneous determination of unecritinib (TQ-B3101) and its active metabolite crizotinib in rat plasma by LC-MS/MS:An application to pharmacokinetic studies.
- Source :
-
Journal of Pharmaceutical & Biomedical Analysis . Aug2024, Vol. 246, pN.PAG-N.PAG. 1p. - Publication Year :
- 2024
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Abstract
- Unecritinib (TQ-B3101) is a selective tyrosine kinase receptor inhibitor. In the study, in vitro metabolic experiments revealed that the hydrolysis of TQ-B3101 was mainly catalyzed by carboxylesterase 2 (CES2), followed by CES1. Next, a sensitive and reliable LC-MS/MS method was established for the simultaneous determination of TQ-B3101 and its metabolite crizotinib in rat plasma. To prevent in vitro hydrolysis of TQ-B3101, sodium fluoride, the CESs inhibitor at a concentration of 2 M , was immediately added after whole blood collection. Plasma samples were extracted by acetonitrile-induced protein precipitation method, and chromatographically separated on a Gemini C 18 column (50 mm × 2.0 mm i.d., 5 μm) using gradient elution with a mobile phase of 0.1% formic acid and 5 mmol/L ammonium acetate with 0.1% formic acid. The retention times for TQ-B3101 and crizotinib were 2.61 and 2.38 min, respectively. The analytes were detected with tandem mass spectrometer by positive electrospray ionization, using the ion transitions at m/z 492.3 → 302.3 for TQ-B3101, m/z 450.3 → 260.3 for crizotinib, and m/z 494.0 → 394.3 for imatinib (internal standard). Method validation was conducted in the linear range of 1.00–800 ng/mL for the two analytes. The precision, accuracy and stabilities all met the acceptance criteria. The pharmacokinetic study indicated that TQ-B3101 was rapidly hydrolyzed to crizotinib with the elimination half-life of 1.11 h after a single gavage administration of 27 mg/kg to Sprague-Dawley rats, and the plasma exposure of TQ-B3101 was only 2.98% of that of crizotinib. • TQ-B3101 is an amide prodrug of crizotinib, a selective tyrosine kinase receptor inhibitor. • First LC-MS/MS method for the simultaneous quantification of TQ-B3101 and crizotinib in rat plasma. • The developed method was successfully applied to a pharmacokinetic study. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 07317085
- Volume :
- 246
- Database :
- Academic Search Index
- Journal :
- Journal of Pharmaceutical & Biomedical Analysis
- Publication Type :
- Academic Journal
- Accession number :
- 177754673
- Full Text :
- https://doi.org/10.1016/j.jpba.2024.116199