HPLC-MS/MS法对氘代沃替西汀氢溴酸盐及其代谢物的检测及大鼠血浆毒代动力学研究

目的:利用HPLC-MS/MS建立大鼠血样中氘代沃替西汀氢溴酸盐(代号JJH201501)及其代谢物(代号JJH201501-01)的检测方法,考察重复给药毒代动力学研究.方法:采用Poroshe11120 EC-C18(4.6 mm × 50 mm,2.7μm),以0.1％甲酸(A)-甲醇(B)为流动相,梯度洗脱,流...

Toxicokinetics of deuterated vortioxetine hydrobromide and metabolites in rat plasma by HPLC-MS/MS

Objective:To establish an HPLC-MS/MS method for the determination of deuterated vortioxetine hydrobromide(JJH201501)and metabolites(JJH201501-01)in rat plasma via oral repeated administration.Methods:The analytes and the internal standard were separated with Poroshell120 EC-C₁₈(4.6 mm×50 mm,2.7μm)by 0.1%formic acid water as mobile phase A and methanol as mobile phase B.The flow rate was 0.6 m L·min^-1.Carbamazepine was used as internal standard.Plasma sample was processed with protein precipitation.Rats were divided into control,low dose,medium dose and high dose group(8,24,80 mg·kg^-1),respectively and administrated orally.Plasma concentration was determined in rats.Results:Deuterated vortioxetine hydrobromide and metabolites could be well detected.The calibration curves were linear in the range of 5.0-1000 ng·mL^-1 for deuterated vortioxetine hydrobromide and metabolites.The selectivity,accuracy,precision,recovery,matrix effect,stability,dilution reliability and residue of the method meet the requirements of methodology validation.It was suitable for the study of toxicokinetics study.The toxicokinetics study showed that exposure(C_{max,AUC_(0-t})of JJH201501 increased significantly or increased in each group of animals,and AUC_0-t of JJH201501-01 in low,medium and high dose groups also increased significantly.In the dose range of 6~60 mg·kg^-1,the increase in AUC_0-t and C_(max of JJH201501 in the first and last treatment was more than the increase in dose.With the exception of the last AUC_0-t,the AUC_0-t and C_(max of JJH201501-01 in the first and last treatment increased out of proportion with the dose.Conclusion:JJH201501 and JJH201501-01 had a tendency of accumulation/accumulation in male and female animals.The toxicokinetics parameters AUC_0-t and C_(max of male and female animals increased disproportionately with the dose(except for the last AUC_0-t of JJH201501-01 in male animals),showing nonlinear dynamic characteristics.