EFFECT OF MICROSOMAL ENZYME INDUCERS ON THE BILIARY EXCRETION OF CARDIAC GLYCOSIDES

¹ Clinical Pharmacology-Toxicoloqy Center, Department of Pharmacology, University of Kansas Medical Center, Kansas City, Kansas

Digitoxin (2.5 mg/kg), digoxin (7 mg/kg) or ouabain (5 mg/kg) was given i.v. to rats pretreated for 4 days with phenobarbital (PB, 50 mg/kg), pregnenolone-16-carbonitrile (PCN, 75 mg/kg), spironolactone (S, 75 mg/kg) or 3-methylcholanthrene (3-MC, 20 mg/kg). Plasma disappearance and biliary excretion of the cardiac glycosides were measured for 2 hours. PCN and S increased the rate of biliary excretion of radioactivity associated with digitoxin by 1000 and 400% respectively. PB-treatment increased the excretion by only 25% and 3-MC decreased it. Similarly with ³H-digoxin, PCN and S increased the rate of biliary excretion of tritium by 400 and 150%, respectively, whereas PB increased it by 25% and 3-MC decreased it. The excretion of radioactivity as polar metabolites in the rats given ³H-digoxin was not increased as has been reported for digitoxin. The increased excretion was due to a more lipid-soluble metabolite, digoxin-bisdigitoxoside, and to the parent compound. PCN, S and PB increased the biliary excretion of ouabain, a cardiac glcoside that is not biotransformed before its excretion, by 150, 50 and 80%, respectively. These studies demonstrate that there is a marked difference in the ability of microsomal enzyme inducers to enhance the biliary excretion of cardiac glycosides and that the mechanism is not solely dependent on biotransformation of the glycoside to more polar metabolites.

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