Embryo-fetal developmental toxicity and toxicokinetics studies of YWS20045 orally administered to pregnant rats

This study aimed to explore the embryo-fetal developmental toxicity and concurrent toxicokinetic characteristics of YWS20045 in rats. Pregnant rats were divided into a solvent control group, three YWS20045 dose groups (4, 16 and 32 mg/kg), and a positive control group (3.5 mg/kg cyclophosphamide). Oral administration was conducted from gestation day (GD) 6-17. Results showed that all dose groups exhibited loose stools, with the high dose group experiencing significant maternal toxicity, including perianal soiling, reduced food intake, weight loss, increased dead fetuses on GD₂₀ and mortality. YWS20045 crossed the placental barrier and accumulated in fetuses at all doses. Doses of 4 mg/kg and above significantly increased fetal rib deformities, affecting fetal growth and development. Toxicokinetic analysis revealed non-proportional increases in C_max and AUC_(0-t) of YWS20045 and its metabolite with dose. The drug was primarily distributed in the liver and lungs, with maternal metabolite mainly in the lungs. Therefore, the relatively safe oral dose of YWS20045 for maternal rats in the embryonic-fetal developmental toxicity study was determined to be 16 mg/kg or lower, whereas doses of 4 mg/kg and above were found to adversely affect fetal growth and development. These findings provide a critical basis for evaluating the reproductive safety of YWS20045 in clinical use.