Embryo-fetal developmental toxicity and toxicokinetics of carenoprazan hydrochloride in rabbits
10.3867/j.issn.1000-3002.2020.07.003
- VernacularTitle: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
- Author:
Bin SHU
1
,
2
;
Yu-Tang ZHANG
;
Ming CAI
;
Qing SHAO
;
Yan-Juan YUAN
;
Jing LIU
;
Hong-Qun QIAO
Author Information
1. 大理大学云南省生物医药研发重点实验室,云南 大理 671000
2. 江苏省药物研究所江苏省药物安全性评价中心,江苏 南京 210009
- Keywords:
carenoprazan hydrochloride;
metabolites;
embryo-fetal developmental toxicity;
New Zealand white rabbits
- From:
Chinese Journal of Pharmacology and Toxicology
2020;34(7):502-510
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE To investigate the embryo-fetal developmental toxicity (EFDT) of careno?prazan hydrochloride (KFP-H008) in rabbits. METHODS Pregnant rabbits were given by gavage KFP-H008 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.
