Teratogenic action of carbonic anhydrase inhibitors in the rat.

Acetazolamide and ethoxzolamide incorporated into the diet of pregnant rats at 0.3% or 0.6% level caused localized appendicular malformation typically affecting the distal, postaxial part of the right forelimb. Other malformations and intrauterine death were also more frequent than in the offspring of untreated rats. Treatment on day 10 or 11 of gestation with 1000 mg/kg of acetazolamide injected subcutaneously also produced a high incidence of typical abnormalities but similar treatment on day 9 or 12 failed to do so. The susceptible period of rat embryos to this agent is thus defined as the tenth and eleventh days. Analysis of maternal blood after teratogenic treatment revealed that both acetazolamide and ethoxzolamide produced metabolic acidosis but little change in other electrolytes except potassium, which was sharply reduced. It was not possible to prevent the occurrence of characteristic malformations by supplemental dosing with potassium. The production of litters with acetazolamide-induced defects was associated with loss of maternal weight after treatment exceeding 10% of pretreatment weight. It has not been possible to produce typical defects using the potent diuretic furosemide. Analysis of embryos from untreated females revealed that carbonic anhydrase does not appear in measurable amounts in the developing rat until the thirteenth day of gestation, making highly unlikely the possibility that the drug's teratogenic action is associated with carbonic anhydrase inhibition in the embryo.