Abstract

The 24-hour LD50 of ouabain in six-week-old rats is approximately 125 mg/kg while ouabain is about 40 times more toxic in 3-day-old rats (3.4 mg/kg). There was a gradual increase in the LD50 from 3 to 12 days of age and a marked increase in the LD50 between 12 and 21 days. After 30 days of age, the LD50 values remained relatively constant. In an attempt to determine the mechanism of the increased sensitivity of the newborn rat to the toxic action of ouabain, the distribution of ³H after the administration of ³H-ouabain (4 mg/kg i.p.) was measured in 7- and 39-day-old rats. The plasma concentration of ouabain was approximately 0.7 µg/ml in the 39-day-old rats and much higher in the 7-day-old rats (5.0 µg/ml). The concentration of ouabain in the liver of the 7-day-old rat was much lower (4 µg/g) than in the liver of the 39-day-old rat (20 µg/g). This increase in the capacity of the liver of the rat to concentrate ouabain and the fall in the plasma ouabain concentration also occurred between 12 and 21 days of age. Therefore, it appears that this inability of the liver of the newborn rat to concentrate ouabain over the plasma results in a higher plasma concentration of ouabain in the newborn rat and a higher toxicity. Thus, it has been demonstrated that the immaturity of the hepatic excretory mechanism is another factor why drugs are more toxic in newborn than adult rats.