A sensitive LC-MS/MS method for simultaneous determination of cabozantinib and its metabolite cabozantinib N-oxide in rat plasma and its application in a pharmacokinetic study.
Biomed Chromatogr
; 32(7): e4227, 2018 Jul.
Article
em En
| MEDLINE
| ID: mdl-29500905
ABSTRACT
Cabozantinib (CBZ) is used for the treatment of progressive, metastatic medullary thyroid cancer. Its major oxidative metabolite is cabozantinib N-oxide (CBN), which contains a structural alert associated with mutagenicity, yet the pharmacokinetics studies lack the simultaneous investigation of CBN and dose proportionality. In the current study a simple LC-MS/MS method was developed and validated for the simultaneous estimation and pharmacokinetic investigation of CBZ and CBN in rat plasma. The analytes were separated on a Waters Atlantics C18 column (2.1 × 150 mm, 3 µm). The mass spectrometry analysis was conducted in positive ionization mode with multiple reaction monitoring. Good linearity was observed over the concentration ranges of 0.500-5000 ng/mL for CBZ and 0.525-2100 ng/mL for CBN. The extraction recoveries were constant and the intra- and inter-batch precision and accuracy were acceptable for the analysis of biological samples. The method was successfully applied for the simultaneous estimation of CBZ and CBN in a pharmacokinetic study in Sprague-Dawley rats. After oral administration of CBZ (1, 5 and 12.6 mg/kg), although CBZ showed dose proportionality, the metabolite CBN showed obvious nonlinear elimination pharmacokinetics with greater than dose-proportional increases in exposure.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piridinas
/
Cromatografia Líquida
/
Espectrometria de Massas em Tandem
/
Anilidas
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Biomed Chromatogr
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
China