盐酸柯诺拉赞的胚胎-胎仔发育毒性

Embryo-fetal development toxicity of carenoprazan hydrochloride

柯诺拉赞为新型质子泵抑制剂沃诺拉赞-的结构类似物,具有相似的作用机制,但其用于孕期的安全性尚不明确。针对此,考察灌胃给予盐酸柯诺拉赞对大鼠胚胎-胎仔发育的影响及进行伴随的毒代动力学研究。将孕鼠随机分为溶剂对照组、阳性对照组(3. 8 mg/kg注射用环磷酰胺)和盐酸柯诺拉赞低、中、高剂量组(20,60,200 mg/kg),在妊娠期(gestation day,GD) 6～15时经口给药,GD 20时处死大鼠。观察并记录大鼠母体在孕期体重、增重及耗食量,有孕的子宫、胎盘总重、黄体数、着床数、活胎数、死胎和吸收胎数等,活胎的外观、身长、体重以及其骨骼和内脏的发育情况。同时检测盐酸柯诺拉赞在卫星组孕鼠血浆中原形和代谢产物的浓度及其在孕鼠和胎鼠体内的组织分布。结果发现,高剂量(200 mg/kg)组动物GD 10～16的耗食量、体重及体重增加值均小于溶剂对照组(P <0. 05);同期,中剂量(60 mg/kg)组动物体重及增重方面也有相似变化(P <0. 05)。高剂量组胎鼠顶臀长度明显较溶剂对照组短(P <0. 05),高、中剂量组胎鼠产生的骨骼发育变异情况也较溶剂对照有明显增加(P <0. 05)。在20～200 mg/kg剂量范围内,单次给予盐酸柯诺拉赞后的原形药物在孕鼠血浆内c_(max)呈线性动力学特征。此外,盐酸柯诺拉赞及其代谢产物均可透过胎盘屏障,且胎鼠体内的脏器分布趋势与母体相近。原形药物和代谢产物在胎鼠体内均以肝脏含量最高。在本试验条件下,20 mg/kg的盐酸柯诺拉赞未对母体和胎鼠发育产生明显毒性。而60和200 mg/kg剂量下所产生的致畸作用可能与药物可透过胎盘屏障有关。

Carenoprazan has the similar structure and mechanism with the potassium-competitive blocker vonoprazan.Howerver,its safety during the pregnancy remains uncertain.To study the embryo-fetal development toxicity and toxicokinetics of carenoprazan hydrochloride via oral administration,time-mated Sprague-Dawley rats were divided into5groups,treated with normal saline,cyclophosphamide for injection(3.8mg/kg),and carenoprazan hydrochloride(20,60,200mg/kg),respectively.Administrated orally from gestation day(GD)6-15.At the termination(GD20),pregnant dams were sacrificed,and concentrations of carenoprazan hydrochloride as well as its metabolite in plasma and issues of both maternal and fetus were examined.As a result,the body weight gain of maternal in both high(200mg/kg)and medium(60mg/kg)dose as well as the food consumption of high-dose were decreased during GD10-16.At the high dose group,decrease of crown rump length of fetuses were significant.Also,skeletal malformation/variations of fetus increased obviously at both high-and medium-dosage.The toxcicokinetics of carenoprazan hydrochloride are linear after single treatment between20-200mg/kg.The placental barrier was penetrated by carenoprazan hydrochloride and metabolite,and the distribution of metabolite in organs were similar in both maternal and fetus,with the highest concentration in livers.Therefore might resulted in the development toxicity.The No Observed Adverse Effect Level(NOAEL)of carenoprazan hydrochloride for both maternal and fetal was20mg/kg.