© 1994 Oxford University Press
research-article |
Developmental Toxicity Studies in Mice, Rats, and Rabbits with the Anticonvulsant Gabapentin
Parke-Davis Pharmaceutical Research, Division of Warner-Lamberi Co. Ann Arbor, Michigan 48105
Received June 16, 1993; accepted May 4, 1994
The developmental toxicity of the anticonvulsant agent gabapentin was evaluated in mice, rats, and rabbits treated by gavage throughout organogenesis. Mice received 500, 1000, or 3000 mg/kg on gestation days (GD) 6–15 and rats and rabbits received 60, 300, or 1500 mg/kg on GD 6–15 (rats) or 6–18 (rabbits). Additional groups received an equivalent volume of the vehicle, 0.8% methylcellulose, or remained untreated. All dams were observed daily for clinical signs of toxicity. In mice, body weights and food consumption were recorded on GD 0, 6, 12, 15, and 18 while in rats and rabbits these parameters were evaluated daily. Near term (mouse, GD 18; rat, GD 20; and rabbit, GD 29) each female was euthanatized, necropsies were performed, and litter and fetal data were collected. Live fetuses were examined for external, visceral, and skeletal variations and malformations. No adverse maternal or fetal effects were observed in mice or rats given doses up to 1500 or 3000 mg/kg, respectively. No treatment-related maternal or fetal effects were apparent in rabbits given 60 or 300 mg/kg. At 1500 mg/kg, one rabbit died, four others aborted, and reduced food consumption and body weight gain were observed. No other reproductive, litter, or fetal parameters were affected, except that the incidence of visceral variations in rat fetuses was slightly but statistically significantly increased at 1500 mg/kg due to a slight increase in the incidence of dilated renal pelvis. This finding was not considered biologically significant because this degree of variability has been seen in this strain of rats. In conclusion, no evidence of teratogenicity was found for gabapentin at doses up to 3000 mg/kg in the mouse and up to 1500 mg/kg in the rat and rabbit.