期刊
出版社
ELSEVIER
DOI: 10.1016/j.jchromb.2020.122176
关键词
Venetoclax; UHPLC-MS/MS; Pharmacokinetics; Mouse plasma
资金
- Ohio State University Comprehensive Cancer Center Pelotonia foundation
- Pelotonia Fellowship Program
A rapid and sensitive analytical method was developed to quantify venetoclax, an oral BH3-mimetic that blocks the anti-apoptotic protein BCL-2, in mouse plasma using ultra-high-performance liquid chromatography with electrospray ionization tandem mass spectrometric detection. Plasma protein precipitation was performed on 5 mu L samples, and separation of the analytes was accomplished on an Accucore aQ column using gradient elution at a flow rate of 0.4 mL/min. The calibration curve was linear (R-2 >= 0.99) over the concentration range of 5-1,000 ng/mL, and the lower limit of quantitation was 5 ng/mL. The intra-day and inter-day precisions (RSD%) were < 10.5%, and accuracies ranged from 94.4 to 106%. The developed method was successfully applied to pharmacokinetic studies involving serial 30 mu L blood sampling from male and female mice after oral administration of venetoclax (10 mg/kg) alone or 30 min after oral administration of ketoconazole (50 mg/kg) or vehicle (PEG400). The observed pharmacokinetic profiles suggest venetoclax undergoes sexually dimorphic disposition in mice. However, regardless of sex, pharmacokinetic studies demonstrated that venetoclax AUC((0-6h)) was increased greater than 2-fold with prior administration of ketoconazole. Overall, our pharmacokinetic studies suggest that mice could be a translationally relevant model for the characterization of venetoclax pharmacokinetics. We have developed an analytical method suitable for such murine pharmacokinetic studies.
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