Embryo lethality and teratogenicity of a new fluoroquinolone antibacterial DW-116 in rats

Abstract

DW-116, 1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-l-piperazinyl)-1, 4-dihydro-4-oxoquinolone-3-carboxylic acid hydrochloride, is a newly developed fluoroquinolone antibacterial. The potential of DW-116 to induce developmental toxicity was investigated in Sprague-Dawley rats. DW-116 was administered by gavage to pregnant rats from days 6 to 16 of gestation at dose levels of 0, 31.3, 125, and 500 mg/kg per day. All dams were subjected to caesarean section on day 20 of gestation and their fetuses were examined for external, visceral and skeletal abnormalities. At 500 mg/kg, toxic effects including clinical signs of toxicity, suppressed body weight and decreased food intake were found in dams. An increase in the resorption rate, a decrease in the litter size, a reduction in the fetal weight, and a decrease in the placental weight were also seen. In addition, various types of external, visceral, and skeletal malformations occurred at an incidence of 17.9, 74.2 and 8.3%, respectively. Characteristic malformations included oedema, cleft palate, dilated cerebral ventricle, hypoplasia of lung and ventricular septum defect. A dramatic increase in the incidence of skeletal variations (55.6%) and retardations (94.4%) and a decrease in the number of ossification centres of sternebra, metacarpals, metatarsals and sacrocaudal vertebra were also observed. At 125 mg/kg, a reduction in the placental weight and an increase in the incidence of skeletal variations were found. There were no signs of maternal toxicity or embryotoxicity at 31.3 mg/kg. These results indicate that the fluoroquinolone antibacterial DW-116 is embryotoxic and teratogenic at minimally maternally toxic dose and is minimally embryotoxic at nonmaternally toxic dose in rats.