Evaluation of Repeat Dose Toxicity and Embryo-Fetal Developmental Toxicity of Novel Glucokinase Activator ZYGK1 in Wistar Rats

Abstract

ZYGK1 is a novel small molecule glucokinase (GK) activator. The purpose of this study was to assess the repeated dose toxicity of ZYGK1 in male and female Wistar rats and its effect on pregnancy and embryo-fetal development in pregnant female Wistar rats. ZYGK1 was administered by oral gavage to rats at 15, 30, 60, and 120 mg/kg, once a day, for 28 consecutive days. For studying the effect on pregnancy and embryo-fetal development, ZYGK1 was administered by oral gavage at 60 and 120 mg/kg from gestation day (GD) 6 to 15, to presumed pregnant female Wistar rats. Hypoglycemia was observed at all doses of ZYGK1 in male and female rats in the general toxicity study, but no toxic effects were observed, except partially reversible axonal degeneration in peripheral nerves. ZYGK1 treatment in pregnant female rats caused hypoglycemia and decreased the fetal body weight. Treatment from GD 6 to 15 caused no significant fetal abnormalities, except incidental fetal skeleton anomalies. Thus, ZYGK1 may lead to maternal hypoglycemia, but no significant developmental toxicity was observed.