Determination of QLNC-3A6 in canine plasma by UHPLC-MS/MS and its application in pharmacokinetic studies.

Abstract

Multi-targeted tyrosine kinase inhibitor QLNC-3A6 Di-maleate, a structurally novel small molecule compound, has therapeutic efficacy for the treatment of canine cutaneous mast cell tumor (CMCT) caused by mutations in the c-Kit gene. Since pharmacokinetic (PK) information plays an important role in the development and application of new drugs, etc., a rapid, highly sensitive and selective UHPLC-MS/MS analytical method was developed and validated for the first time in this study for the quantitative detection of QLNC-3A6 in canine plasma. 100 µL of plasma was precipitated using 350 µL of acetonitrile, and Chromatographic separation was performed on a Phenomenex Kinetex C18 column (50 × 2.1 mm, 2.6 µm) at a flow rate of 0.4 mL/min, the mobile phases were set to 0.1% formic acid aqueous solution (A) and 0.1% formic acid acetonitrile (B). The calibration curve linear range was 0.5-100 ng/mL (R²>0.99). The intraday and interday precision values (relative standard deviation, RSD) were 2.06-13.57% and 6.90-9.14%. Intraday and interday accuracies were -10.73 to 9.54% and -3.86 to 0.70% respectively. The dilution integrity RSD value and stability RSD value were less than 3.77 and 7.45%, respectively. Subsequently, the pharmacokinetics were investigated in canine after oral administration of QLNC-3A6 Di-maleate tablets at a dose of 3 mg/kg BW using this method. The results showed that QLNC-3A6 showed fast absorption rate, rapid distribution and slow metabolic elimination in canine plasma. The results of the main PK parameters including λz, T_1/2λz, C_max, T_max and AUC_last were 0.07 ± 0.01/h, 11.00 ± 2.57 h, 50.88 ± 31.94 ng/mL, 9.08 ± 11.57 h and 836.48 ± 230.53 ng h/mL, respectively.