On the glucuronidation of digitalis compounds in different species

Experiments were undertaken to evaluate for various species the activity and specificity of the glucuronyltransferase(s) which are responsible for the conjugation of digitoxin or its metabolites formed by oxidative cleavage of the sugar chain. As shown for rats the glucuronide of digitoxigenin monodigitoxoside is the main polar digitoxin metabolite in vivo. However, it cannot be decided whether this digitoxoside or another metabolite is the best substrate for the glucuronyltransferase. Therefore, in vitro measurements were made with possible cleavage products of digitoxin using detergent activated liver microsomes. Digitoxigenin monodigitoxoside is by far the best substrate for the microsomal glucuronyltransferase of rats (120 pmoles/mg/min). Ten-fold lower values were found with digitoxigenin bisdigitoxoside and only traces of glucuronides were formed with digitoxin, digitoxigenin or its 3-epimer. With liver microsomes of other species the glucuronidation rates for digitoxigenin monodigitoxoside decreased in the following order: rat greater than rabbit greater than guinea-pig greater than cat (1:0.3:0.2:0.05). For rabbit liver microsomes, however, the best substrate was the 3-epi-digitoxigenin instead of the monodigitoxoside (145 pmoles/mg/min). Experiments with tissue slices of liver and small intestine revealed further differences between rats and rabbits. Whereas rat intestine was nearly inactive the activity of rabbit intestine attained about 50% of that found in the liver. It can be concluded that various species show remarkable differences in the activity, stereospecificity and organ distribution of the glucuronyltransferase(s) conjugating cardenolide derivatives.