The cardioactive metabolites of digitalis glycosides.

There is little known about the nature of the metabolic products derived from cardiac glycosides in the animal body. Reports of the formation of digitoxigenin from the glycoside digitoxin in vivo have appeared in the literature (l-3), but reliable chemical methods of identification applicable to the very small quantities of material involved were not available to these workers. Fischer, Sjoerdsma, and Johnson (4) examined the urinary excretion of digitoxin in rats by the use of the radioactive glycoside and distinguished between digitoxin and its metabolites on the basis of the chloroform solubility of digitoxin. However, no further chemical investigation of the radioactive metabolites was made. The cardiac glycosides, digoxin, digitoxin, and lanatoside C, have been shown by previous work in this laboratory to be excreted in the urine of rats partly as the original glycoside and partly in the form of cardioactive metabolites. Digoxin yielded a metabolite, Metabolite B, which was not digoxigenin but which retained the unsaturated lactone ring characteristic of cardiac glycosides (5). Lanatoside C also produced this metabolite in urine, together with some digoxin and unchanged lanatoside C. Digitoxin was converted to an apparently more polar metabolite (6) which we have now named Metabolite C. This was not digitoxigenin. In the case of digit,oxin, Metabolite C appeared to be the main cardioactive substance excreted in the urine, as only small amounts of the free glycoside could be detected. Because of the extremely small amounts excreted by the rat, it has not yet been possible to obtain sufficient of these metabolites for a normal chemical investigation. This paper describes some experiments, conducted mainly by paper chromatographic methods, which reveal some information about the chemical nature of these substances.