Increased digitoxin cleavage by liver microsomes of spironolactone-pretreated rats.
Pretreatment of rats with spironolactone caused an fourfold increased cleavage rate of the sugar chain of digitoxin (dt-3) in vitro yielding digitoxigenin-bis-digitoxoside. This was due to an enhanced, cyt. P450 dependent, formation of 15'-dehydro-dt-3, the intermediate which has to be formed before the terminal sugar can be split off. The second reaction catalysed by microsomal monoxygenases, the 12-beta-hydroxylation, was only increased by a factor 2. In contrast to the effects of spironolactone no increase of metabolism could be observed after phenobarbital pretreatment. From our results it may be concluded that the enhanced dt-3 metabolism in vivo is mainly caused by spironolactone inducible monoxygenases which catalyse the oxidation of the terminal sugar.
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004074:Digitoxin / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D013148:Spironolactone / Q000494:pharmacology*; D013997:Time Factors
D013148:Spironolactone; D003577:Cytochrome P-450 Enzyme System; D004074:Digitoxin; D010634:Phenobarbital