Impaired biliary excretion of digitoxin and its metabolites after treatment with polychlorinated biphenyls.

In order to study the effects of polychlorinated biphenyls (PCB), potent inducers of microsomal drug-metabolizing enzymes, on the elimination rate of digitoxin (DT-3), the bile of rats were collected for 4 hr after a single dose of tritiated digitoxin ([³H]DT-3). In comparison to normal rats PCB caused a decrease of elimination by 50% whereas phenobarbital (PB) increased the rate by 36%. After extracting the bile with CHCl₃, measurements of radioactivity revealed that PCB-treated rats excreted only 3.2% of the dose as CHCl₃-soluble compounds. The corresponding fraction of both normal and PB-pretreated rats contained about 10% of the dose. The increased DT-3 elimination produced by PB was due to the large amount of water-soluble metabolites (nearly 24% of the dose). Normal and PCB-pretreated rats excreted about 10% water-soluble metabolites. Further analysis of metabolites showed: (1) In addition to the known metabolites (digoxin, bis-, and monodigitoxosides of both digitoxigenin and digoxigenin) the CHCl₃-soluble fraction contained a more lipophilic fraction. It consisted mainly of the dehydro-bis-digitoxoside of digitoxigenin. (2) Free genins could not be found. (3) Digitoxigenin monodigitoxoside was the main substrate for conjugating enzymes. (4) Nearly 30% of water-soluble metabolites were cardenolide acids presumably formed by hydrolysis of the butenolide. The results suggest that after PCB treatment the decreased DT-3 elimination rate is caused at least in part by an impaired digitoxoside cleavage.