To investigate the embryo-fetal developmental toxicity (EFDT) of carenoprazan hydrochloride (KFP-H008) in rabbits.

  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.

  From GD 13, the maternal body mass and the food consumption in KFP-H008 15 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-H008 15 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-H008 50 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-H008 15 mg·kg^-1 group, KFP-H008 and its metabolites were undetectable in most of maternal and fetal tissues.

  The no observed adverse effect level (NOAEL) of KFP-H008 for maternal and fetal rabbits is about 5 mg·kg^-1.