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.
ABSTRACT
@#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 into 5 groups, treated with normal saline, cyclophosphamide for injection(3. 8 mg/kg), and carenoprazan hydrochloride(20, 60, 200 mg/kg), respectively. Administrated orally from gestation day(GD)6 - 15. At the termination(GD 20), 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(200 mg/kg)and medium(60 mg/kg)dose as well as the food consumption of high-dose were decreased during GD 10-16. 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 between 20-200 mg/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 was 20 mg/kg.