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 Poroshell120 EC-C18（4.6 mm×50 mm,2.7 μm）,以 0.1% 甲酸（A）-甲醇（B）为流动相,梯度洗脱,流速 0.6 mL·min-1;甲醇蛋白 沉淀法提取;卡马西平为内标定量。将大鼠随机分为溶媒对照组和低、中、高剂量组（8、24、80 mg·kg-1）,经口给药,检测大鼠血药浓度。结果：氘代沃替西汀氢溴酸盐及其代谢物均能很好检出,其线性范围均为 5.0~1 000 ng·mL-1,呈良好的线性关系。该方法的选择性、准确度、精密度、提取回收率、基质效应、稳定性、 稀释可靠性、残留均符合方法学验证要求。毒代动力学研究表明：JJH201501 在各组动物体内的暴露（Cmax、AUC0-t）显著增加或有增高的趋势;低、中、高剂量组 JJH201501-01 的 AUC0-t 亦显著增加。在 6~60 mg·kg-1 剂量范围内,首末次各剂量组 JJH201501 的 AUC0-t、Cmax 增长的幅度大于剂量的增加;JJH201501-01 除末 次 AUC0-t 外,首末次各剂量组 JJH201501-01 的 AUC0-t、Cmax 均与剂量不成比例增加。结论：JJH201501 及 JJH201501-01 在雌雄动物体内均存在蓄积的趋势;雌雄动物毒代动力学参数 AUC0-t、Cmax 均与剂量不成比例 的增加（雄性动物JJH201501-01 末次 AUC0-t 除外）,呈非线性动力学特征。
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,2.7 μm）by 0.1% formic acid water as mobile phase A and methanol as mobile phase B. The flow rate was 0.6 mL·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（Cmax,AUC0-t）of JJH201501 increased significantly or increased in each group of animals,and AUC0-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 and C0-tmax of JJH201501 in the first and last treatment was more than the increase in dose. With the exception of the last AUC0-t,the AUC0-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 AUC0-t and C max of male and female animals increased disproportionately with the dose（except for the last AUC0-t of JJH201501-01 in male animals）,showing nonlinear dynamic characteristics.
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