Teratogenic Effects of Sulfonylureas and Insulin in Rats

Abstract

When glibenclamide, tolbutamide and chlorpropamide were orally administered to pregnant rats from day 9 to day 14 of gestation, microphthalmia and/or anophthalmia were induced in the offspring by each of the drugs, although the incidence was low with all three. Subcutaneous administration of long-acting insulin from day 9 to day 11 of gestation also induced similar eye malformations. The frequency of the eye malformation was lower in the offspring of rats receiving glibenclamide on days 6 - 15 of gestation than in those of animals receiving the drug on days 9 - 14 of gestation. No malformations were observed when glibenclamide was given on days 9 - 14 of gestation after a pretreatment with tolbutamide on days 6 - 8 of gestation. The blood glucose level was significantly lowered for more than 24 hr after a single dose of 300mg/kg of glibenclamide, which was quite comparable to the effect of 50 IU/body of insulin. However, when 300mg/kg of glibenclamide was administered for 3 consecutive days, the third dose had much less effect on the blood glucose level than the first one. Our study suggested that the eye malformations induced by the sulfonylureas in the offspring, as well as by insulin, might be closely related to hypoglycemia which was brought about in the maternal rats by the drug administration from day 9.