氟诺哌齐对新西兰家兔胚胎-胎仔发育毒性及毒代动力学  

Embryo-fetal developmental toxicity and toxicokinetics of fluoropezil in New Zealand rabbits

作　　者：毛闪闪 李芳[2,3] 蔡桂红 朱云凯 许旭 崔艳君 周文 曹敏 周莉 MAO Shanshan;LI Fang;CAI Guihong;ZHU Yunkai;XU Xu;CUI Yanjun;ZHOU Wen;CAO Min;ZHOU Li(Wuhan Branch Hubei Topgene Biotechnology Co.,Ltd.,Wuhan 430075,China;Jiangsu Kanion Pharmaceutical Co.,Ltd.,Lianyungang 222000,China;National Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture,Lianyungang 222000,China)

机构地区：[1]湖北天勤生物科技股份有限公司武汉分公司,湖北武汉430075 [2]江苏康缘药业股份有限公司,江苏连云港222000 [3]中药制药过程控制与智能制造技术全国重点实验室,江苏连云港222000

出　　处：《中国药理学与毒理学杂志》2024年第2期120-127,共8页Chinese Journal of Pharmacology and Toxicology

摘　　要：目的研究氟诺哌齐(fronopezil)对新西兰家兔胚胎-胎仔发育的影响及其伴随毒代动力学,为临床用药提供参考。方法按妊娠顺序将孕兔分为溶媒(1%羟丙基甲基纤维素+1.5%聚乙二醇400水溶液)对照组、环磷酰胺(18 mg·kg^(-1),阳性对照)组及氟诺哌齐3.6,9.0和22.5 mg·kg^(-1)组。溶媒对照组和氟诺哌齐组于妊娠第6~18天(GD6-18)ig给药,环磷酰胺组于GD6-20 ig给药。GD_(28)处死孕兔,检测胚胎-胎仔发育,ELISA检测GD5,GD_(18)和GD_(28)孕兔血清中性激素水平,首末次给药前后采血进行伴随毒代动力学研究,采用高效液相色谱串联质谱法检测血浆、胎仔、胎盘和羊水中的药物浓度。结果氟诺哌齐3.6,9.0和22.5 mg·kg^(-1)对孕兔的体重、增重、摄食量和妊娠结局及胎仔的外观、内脏、骨骼和体格生长发育均未见明显影响;仅在GD_(18)或GD_(28)各剂量组卵泡刺激素、雌二醇和孕酮水平有一定程度波动。伴随毒代动力学研究结果表明,氟诺哌齐可通过胎盘屏障,但在孕兔和胎仔体内无明显蓄积;环磷酰胺组胎仔体重、顶臀长和连胎子宫重均低于溶媒对照组(P<0.01),外观和骨骼均出现畸形。结论氟诺哌齐对新西兰家兔胚胎-胎仔发育毒性的未见有害作用剂量为22.5 mg·kg^(-1),为药效起效剂量的125倍,该剂量下GD_(18)血药峰浓度为1093μg·L^(-1),药时曲线下面积为6650μg·h·L^(-1)。OBJECTIVE To study the effect of fluoropezil on embryo-fetal developmental toxicity and toxicokinetics in rabbits,and provide reference for clinical medication.METHODS According to the sequence of pregnancy,pregnant rabbits were divided into five groups:vehicle control group(1%hydroxy⁃propyl methylcellulose+1.5%polyethylene glycol 400 aqueous solution),positive control group(cyclo⁃phosphamide 18 mg·kg^(-1)),and fluoropezil(3.6,9.0 and 22.5 mg·kg^(-1))groups.The vehicle control group and the fluoropezil groups were ig administrated on the 6th to 18th day of gestation(GD6-18)while the positive control group was ig given cyclophosphamide on GD6-20.The pregnant rabbits were sacri⁃ficed on GD_(28),and the embryo-fetal development was detected.Sex hormone levels of pregnant rabbits on GD5,GD_(18)and GD_(28)were detected by ELISA method.Blood samples with toxokinetics were collected for concomitant toxic generation at the first and last administration,and drug concentrations in fetal,placenta and amniotic fluid were detected with liquid chromatography tandem mass spectrometry(LC-MS/MS).RESULTS Fluoropezil 3.6,9.0 and 22.5 mg·kg^(-1)had no significant effect on body mass,mass gain,food consumption,pregnancy outcomes,fetal appearance,viscera,skeletal and physical growth and development of pregnant rabbits.Only on GD_(18)or GD_(28),the levels of follicle stimulating hormone,estra⁃diol and progesterone in each dose group fluctuated to some extent.The combined toxokinetics results indicated that fluoropezil could cross the placental barrier of the rabbits,but did not accumulate in preg⁃nant rabbits or fetuses.Fetal mass,crown-rump length and uterus mass in the cyclophosphamide group were lower than those in the vehicle control group.The appearance and bone of the cyclophos⁃phamide group were positive.CONCLUSION The no observed adverse effect level(NOAEL)of fluoro⁃pezil toxicity on rabbit embryo-fetal development is 22.5 mg·kg^(-1),which is 125 times of the effective dose.At the dosage level of 22.5 mg·kg^(

关 键 词：家兔 氟诺哌齐 胚胎-胎仔发育 生殖毒性 

分 类 号：R394.6[医药卫生—医学遗传学] R969.1[医药卫生—基础医学] R99