盐酸柯诺拉赞对新西兰白兔的胚胎-胎仔发育毒性及其毒代研究

Embryo-fetal developmental toxicity and toxicokinetics of carenoprazan hydrochloride in rabbits

目的研究盐酸柯诺拉赞(KFP-H008)对新西兰白兔的胚胎-胎仔发育毒性。方法将盐酸柯诺拉赞(KFP-H008)5,15和50 mg·kg^-1于新西兰白兔妊娠第6~18天(GD 6~18,致畸敏感期)ig给予孕兔,同时设立溶媒对照组和阳性对照组(环磷酰胺10 mg·kg^-1,iv),观察并记录母体在孕期体质量和耗食量。在GD 29对孕兔实施安乐死,记录妊娠子宫、胎盘总重、黄体数、着床数、活胎数、死胎和吸收胎数等。观察并记录活胎的外观、身长、体质量,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兔血浆中原形和代谢产物的浓度及其在孕兔和胎兔体内的组织分布。结果从GD 13开始,KFP-H00815和50 mg·kg^-1组孕兔体质量和耗食量低于对照组(P<0.05)。同时上述各组胎兔的顶臀长和体质量均明显减少(P<0.05),且可见骨骼畸形或变异。KFP-H008单次给药后被迅速代谢,在母体血浆中几乎检测不到。重复多次给药后,KFP-H00850 mg·kg^-1组母体和胎仔组织中均检出了药物原形和代谢产物,这可能是导致胎兔出现致畸作用的原因;而KFP-H00815 mg·kg^-1组,多个组织中药物原形和代谢产物均未能检出。结论KFP-H008对新西兰白兔母体及胎仔不产生明显毒性的剂量为5 mg·kg^-1。

OBJECTIVE To investigate the embryo-fetal developmental toxicity(EFDT)of careno⁃prazan hydrochloride(KFP-H008)in rabbits.METHODS Pregnant rabbits were given by gavage KFPH008 at 5,15 and 50 mg·kg^-1 during the organogenetic period(gestation days 6-18,GD 6-18).Rabbits in positive control group were treated with cyclophosphamide(CP)10 mg·kg^-1 by iv.Maternal body mass and food consumption during gestation were recorded.Pregnant dams were euthanized on GD 29.The numbers of live/dead fetuses,resorptions,implantations,corpora lutea,and gravid uterus mass,placenta mass,fetal gender ratios,body mass,and skeletal development were evaluated.Moreover,the toxicokinetic parameters including AUC and C0-t,and tissue distributions were determined.RESULTS From GD 13,the maternal body mass and the food consumption in KFP-H00815 and 50 mg·kg^-1 groups were lower than in the normal control group(P<0.05).Also,the reduced fetal crown rump length and mass,skeletal malformations/variations were observed in KFP-H00815 and 50 mg·kg^-1 groups(P<0.05).KFP-H008 was rapidly eliminated,and became undetectable in the maternal plasma after a single administration.Following multiple KFP-H00850 mg·kg^-1 treatment,both KFP-H008 and its metabolites were detectable in various tissues of the maternal and fetus,which might be the evidence for carenoprazan-induced developmental toxicity.In KFP-H00815 mg·kg^-1 group,KFP-H008 and its metabolites were undetectable in most of maternal and fetal tissues.CONCLUSION The no observed adverse effect level(NOAEL)of KFP-H008 for maternal and fetal rabbits is about 5 mg·kg^-1.