Comparison of the toxicity of chemicals in newborn rats to bile duct-ligated and sham-operated rats and mice

Abstract

Marked differences were observed in the effect that bile duct ligation (BDL) had on the toxicity of compounds. For amitryptiline, glutethimide, bishydroxycoumarin, digitoxin, fluorescein, guanethidine, novobiocin, pentobarbital, probenecid, quinine, and taurocholic acid, the 24-hr LD50 values in the BDL mice were similar to those in control mice. However, nafcillin, sulfobromophthalein and its dibrominated analog, phenol-3,6-dibromophthalein disulfonate, had a potency ratio between 1.5 and 2 and thus were moderately more toxic in BDL mice. A number of compounds were much more toxic in BDL than in sham-operated mice: digoxin was 2.1, azorubin S 2.2, rifampin 2.6, ouabain 4.4, colchicine 4.6, indocyanine green 7.6, iopanoic acid 5.1 and diethylstilbestrol 24 times more toxic in BDL mice than in sham-operated mice. Most of the chemicals that were more toxic in the BDL mice than in their respective controls were also more toxic in BDL rats: probenecid was 1.7, colchicine 1.8, iopanoic acid 2.2, rifampin 2.4, ouabain 3.9, digoxin 4.2, indocyanine green 5.4 and diethylstilbestrol 130 times more toxic in BDL than in sham-operated rats. Of these 8 chemicals that were more toxic in BDL rats, 6 were also more toxic in newborn rats than in sham-operated rats; probenecid was 2.8, indocyanine green 3.3, iopanoic acid and digoxin 3.8, ouabain 13 and colchicine 21 times more toxic in the newborn than in the adult rats. These results suggest that a decrease in hepatic excretory function does increase the toxicity of some drugs that are normally excreted into the bile and a decrease in hepatic excretory function may be another factor increasing the sensitivity of the newborn to the toxic properties of chemicals.