Potassium loss as a causative factor for skeletal malformations in rats produced by indacrinone: A new investigational loop diuretic

Abstract

Indacrinone (MK-196), an investigational loop diuretic, was administered to female CRCD rats from Days 6 to 17 of gestation at doses of 40, 80, or 120 mg/kg/day. Dose-related increases in wavy ribs and malformations of the scapula and humerus were apparent in fetuses from all drug-treated groups. Studies on the individual enantiomers of MK-196 showed that the teratogenic potency was associated with the relative saluretic activity of the enantiomers. Furosemide, a widely used diuretic with pharmacologic activity similar to that of MK-196, was administered to rats on Days 6 to 17 at doses of 37.5, 75, 150, or 300 mg/kg b.i.d. Dose-related increases in wavy ribs occurred in all drug treatment groups. At 150 mg/kg b.i.d. there were malformations in the scapula and humerus identical to those described for MK-196. Providing a 1% solution of KCl during the dosing period reduced the incidence of wavy ribs in fetuses from MK-196-treated dams by 90% and eliminated the scapular and humeral malformations. Coadministration of amiloride was also found to antagonize the teratogenicity of MK-196. The results indicate that high doses of diuretics with similar pharmacologic activities can produce identical skeletal malformations in rats, and that this teratogenicity is related to hypokalemia.