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
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摘要
目的考察灌胃给予氘代沃替西汀氢溴酸盐(DVH)对大鼠胚胎-胎仔发育的影响及其毒动学。方法将孕鼠随机分为溶媒组、阳性对照组(3. 8 mg·kg~(-1)注射用环磷酰胺)和DVH组(低、中、高剂量分别为8、24、80 mg·kg~(-1)DVH),在妊娠GD 6～GD 15时灌胃给药,GD 20时处死大鼠,记录各项指标,并检测母鼠的血药浓度以及DVH在孕鼠和胎仔(胎鼠)体内的组织分布。结果 DVH呈现线性药动学特征。DVH及其羧基代谢产物可透过胎盘屏障,胎仔体内的脏器分布趋势与母体相近,DVH及其羧基代谢产物在胎仔肝脏中的含量最高、肾脏、肺脏次之,高剂量组出现的发育毒性可能与其相关。结论在试验条件下,24 mg·kg~(-1)DVH未对孕鼠母体产生明显毒性,8 mg·kg~(-1)DVH未对胎仔产生明显毒性。
OBJECTIVE To study the embryo-fetal development toxicity and toxicokinetics of deuterated Vortioxetine hydrobromide( DVH) via oral administration. METHODS Pregnant rats were divided into 5 groups,treated with normal saline,cyclophosphamide for injection( 3. 8 mg·kg~(-1)),and DVH( 8,24,and 80 mg·kg~(-1) DVH) respectivly and administrated orally in GD 6-GD 15. Rats were sacrificed on GD 20,and concentrations of DVH as well as its metabolites in plasma and tissues of both maternal and fetal were determined. RESULTS The toxcicokinetics of DVH are linear. The placental barrier was penetrated by DVH and metabolites,and the distribution in organs were similar in maternal and fetal,with the highest concentration in livers. Therefore might resulted in the development toxicity. CONCLUSION The no observed adverse effect level of DVH for maternal is 24 mg·kg~(-1),and for fetal is8 mg·kg~(-1).
OBJECTIVE To study the embryo-fetal development toxicity and toxicokinetics of deuterated Vortioxetine hydrobromide( DVH) via oral administration. METHODS Pregnant rats were divided into 5 groups,treated with normal saline,cyclophosphamide for injection( 3. 8 mg·kg~(-1)),and DVH( 8,24,and 80 mg·kg~(-1) DVH) respectivly and administrated orally in GD 6-GD 15. Rats were sacrificed on GD 20,and concentrations of DVH as well as its metabolites in plasma and tissues of both maternal and fetal were determined. RESULTS The toxcicokinetics of DVH are linear. The placental barrier was penetrated by DVH and metabolites,and the distribution in organs were similar in maternal and fetal,with the highest concentration in livers. Therefore might resulted in the development toxicity. CONCLUSION The no observed adverse effect level of DVH for maternal is 24 mg·kg~(-1),and for fetal is8 mg·kg~(-1).
引文
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[5]丁德平,李召广,冯琦,等.一种氘代沃替西汀氢溴酸盐的合成方法[P]. CN107513048A. 2017-12-26
[6]岳鹏,沈姣,乔红群,等.注射用左旋泮托拉唑钠对大鼠胚胎-胎仔发育的毒性及伴随毒代动力学研究[J].华西药学杂志,2017,32(6):599-602.
[7]董小帝,翟金国,赵靖平.新型抗抑郁药沃替西汀临床应用新进展[J].精神医学杂志,2016,29(4):308-311.
[8] Chen G,Hojer AM,Areberg J,et al. Vortioxetine:Clinical pharmacokinetics and drug interactions[J]. Clin Pharmacokinet,2018,57(6):673-686.
[9] Connolly KR,Thase ME. Vortioxetine:A new treatment for major depressive disorder[J]. Expert Opin Pharmacother,2016,17(3):421-431.