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.
ZHANG Xiao-lei, YUAN Yan-juan, SHAO Qin, ZHOU Bo, LIU Jing
. Toxicokinetics of deuterated vortioxetine hydrobromide and metabolites in rat plasma by HPLC-MS/MS[J]. Chinese Journal of Pharmaceutical Analysis, 2021
, 41(2)
: 253
-262
.
DOI: 10.16155/j.0254-1793.2021.02.09
[1] GIBB A,DEEKS ED.Vortioxetine:first global approval[J]. Drugs,2014,74(1):135
[2] HVENEGAARD M,ANDERSEN BB,PEDERSEN H,et al.Identification of the cytochrome P450 and other enzymes involved in the in vitro oxidative metabolism of a novel antidepressant[J].Drug Metab Dispos,2012,40(7):1357
[3] BAUNE BT,SLUTH LB,OLSEN CK.The effects of vortioxetine on cognitive performance in working patients with major depressive disorder:a short-term,randomized,double-blind,exploratory study[J].J Affective Disord,2018,229 :421
[4] SANCHEZ C,ASIN KE,ARTIGAS F.Vortioxetine,a novel antidepressant with multimodal activity:review of preclinical and clinical data[J].Pharmacol Ther,2015,145 :43
[5] VIETA E,SLUTH LB,OLSEN CK.The effects of vortioxetine on cognitive dysfunction in patients with inadequate response to current antidepressants in major depressive disorder:a short-term, randomized,double-blind,exploratory study versus escitalopram[J].J Affective Disord,2018,227 :803
[6] 杨飞瀑,何洋,王震,等.抗精神分裂症药物研究进展[J].药学学报,2016,51(12):1809
YANG FP,H E Y ,W ANG Z ,e t al .R esearch progress of antipsychotics[J].Acta Pharm Sin,2016,51(12):1809
[7] NOMIKOS GG,TOMORI D,ZHONG W,et al.Efficacy,safetyand tolerability of vortioxetine for the treatment of major depressive disorder in patients aged 55 years or older[J].CNS Spect,2017, 22(4):348
[8] 刘洁. 氘代药物进展[J].医药化工,2016,42(4):199
LIU J.Deuterated drugs progress[J].Pharm Chem,2016,42(4): 199
[9] CHEN G,LEE R,HOJER AM,et al.Pharmacokinetic drug interactions involving vortioxetine,a multimodal antidepressant[J]. Clin Drug Invest,2013,33(10):727
[10] MORK A,PEHRSON A,BRENNUM LT,et al.Pharmacological effects of Lu AA21004:a novel multimodal compound for the treatment of major depressive disorder[J].Pharmacol Exp Ther,2012,340(3):666
[11] AREBERG J,JENSEN ML,SOGAARD B,et al.Occupancy of the serotonin transporter after administration of Lu AA21004 and its relation to plasma concentration in healthy subjects[J].Basic Clin Pharmacol Toxicol,2012,110(4):401
[12] THEUNISSEN EL,STREET D,HOJER AM,et al.A randomized trial on the acute and steady-state effects of a new antidepressant, vortioxetine,on actual driving and cognition[J].Clin Pharmacol Therap,2013,93(6):493
[13] STENKRONA P,HALLDIN P,LUNDBERG J.5-HTT and 5-HT1 areceptor occupancy of the novel substance vortioxetine.A PET study in control subjects[J].Eur Neuropsychopharmcol,2013,23(10):1190
[14] GU EM,HUANG CK,LIANG BQ,et al.An UPLC-MS/MS method for the quantitation of vortioxetine in rat plasma:application to apharmacokinetic study[J].J Chromatogr B,2015,997 :70
[15] 蔡鸣,舒斌,邵卿,等.氘代沃替西汀氢溴酸盐的胚胎-胎仔发育毒性及伴随毒动学研究[J].华西药学杂志,2018,33(6):594
CAI M,SHU B,SHAO Q,et al.The embryo-fetal development toxicity and toxicokinetics of deuterated vortioxetine hydrobromide[J].West China J Pharm Sci,2018,33(6):594
