妇科再造胶囊兔胚胎-胎仔发育毒性伴随毒代动力学研究

Embryo-fetal developmental toxicity and toxicokinetics of Fuke Zaizao Capsules in rabbits

目的:观察妇科再造胶囊对兔胚胎-胎仔发育及其伴随毒代动力学的影响,为临床用药提供参考。方法:孕兔在着床至硬腭闭合期间(GD_(6-18)),灌胃(ig)给予不同剂量的妇科再造胶囊(0.88,2.63和5.25 g·kg^(-1)),溶媒对照组给予纯水;GD_(28)处死孕兔,取胎仔,检查黄体数、胎重(连子宫)、胎仔重量、胎盘重量、活胎数、死胎数(含吸收胎)、胎仔性别、顶臀长、尾长及外观、内脏和骨骼,并计算着床数。分别在GD_(5),GD_(18)和GD_(28)取血清,测定黄体生成素、卵泡刺激素、雌二醇、孕酮和睾酮水平。于首次和末次给药进行伴随毒代采血,检测胎仔、胎盘及羊水中的药物浓度。结果:妇科再造胶囊对孕兔的妊娠期体重和增重、摄食量、妊娠结局、胎仔外观、内脏、骨骼以及体格生长发育均未见明显影响;高剂量组黄体生成素、雌二醇和孕酮水平在GD_(18)有轻微波动;伴随毒代结果可知,妇科再造胶囊可以通过胎盘屏障,但在孕兔和胎仔体内无明显蓄积。结论:妇科再造胶囊对兔胚胎-胎仔发育毒性的无可见有害作用水平(NOAEL)为5.25 g·kg^(-1),为等效剂量的18.5倍,临床剂量的55.4倍。

Objective: To observe the effect of Fuke zaizao Capsule on embryo-fetal developmental toxicity and toxicokinetics in rabbits in order to provide reference for clinical medication. Methods: During the period from implantation to hard palate closure(GD_(6-18)), pregnant rabbits were given different doses of Fuke Zaizao Capsules(0.88, 2.63 and 5.25 g·kg^(-1)) by gavage(ig), and vehicle control group was given pure water. Pregnant rabbits were killed and fetuses were taken in GD_(28). The number of corpus luteum, fetal weight(including uterus), fetal weight, placenta weight, number of live fetuses, number of dead fetuses(including absorption fetuses), sex of fetuses, crown-rump length, tail length, appearance, viscera and skeleton were examined, and the number of implantation was calculated. Serum levels of luteinizing hormone, follicle stimulating hormone, estradiol, progesterone and testosterone were measured in GD_(5), GD_(18)and GD_(28). Blood samples were collected at the first and the last administration, drug concentrations were detected in fetus, placenta and amniotic fluid. Results: Fuke Zaizao Capsule had no significant effect on gestational weight, weight gain, food intake, pregnancy outcome, fetal appearance, viscera, skeleton and physical growth in pregnant rabbits. The levels of luteinizing hormone, estradiol and progesterone in high dose group fluctuated slightly in GD_(18). The toxicokinetics results showed that Fuke Zaizao Capsule passed through the placental barrier without significant accumulation in pregnant rabbits and fetuses. Conclusion: The NOAEL of Fuke Zaizao Capsule on rabbit embryo-fetal development is 5.25 g·kg^(-1), which is 18.5 times of the equivalent dose and 55.4 times of the clinical dose.