Embryo lethality and teratogenicity of a new fluoroquinolone antibacterial DW-116 in rats.
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.
Kim
J C
JC
Reproductive Toxicology Division, Toxicology Research Centre, Korea Research Institute of Chemical Technology, Yusong, Taejon, Republic of Korea. jongckim@pado.krict.re.kr
Yun
H I
HI
Shin
H C
HC
Han
S S
SS
Chung
M K
MK
D000014:Abnormalities, Drug-Induced / Q000209:etiology; D000284:Administration, Oral; D000818:Animals; D000890:Anti-Infective Agents / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D001842:Bone and Bones / Q000002:abnormalities / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005260:Female; D005313:Fetal Death / Q000139:chemically induced*; D024841:Fluoroquinolones; D008297:Male; D008431:Maternal-Fetal Exchange; D010879:Piperazines / Q000633:toxicity*; D011247:Pregnancy; D015363:Quinolones / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013723:Teratogens / Q000633:toxicity*
D000890:Anti-Infective Agents; C097673:DW-116; D024841:Fluoroquinolones; D010879:Piperazines; D015363:Quinolones; D013723:Teratogens