The metabolites of cardiac glycosides in human urine.

A study of the urinary excretion of digitoxin in man was first attempted by Friedman and coworkers (1) by the use of the embryonic duck heart method of biological assay. These workers estimated that the amount of cardioactive substances (calculated as digitoxin) excreted in the urine of young adults over a period of 12 to 24 days after an oral dose was equivalent to approximately 40 per cent of the dose. However, no differentiation between digitoxin and possible cardioactive metabolites was attempted in this work. By using biosynthetically labeled C14-digitoxin, Okita et al. (2) found that 60 to 80 per cent of an intravenous dose was eliminated through the kidneys of humans over a long period, and that only 6 to 10 per cent of this appeared to be unchanged glycoside. The nature of the metabolites of the glycoside present in the urine was not investigated. Some qualitative information has been obtained about the metabolic products of cardiac glycosides excreted in rat urine (3, 4). Digoxin and lanatoside C were both excreted in this animal, principally as the unchanged glycoside, but both were also converted to a metabolic product which has been designated Metabolite B. Investigation into the chemical nature of this substance (5) indicated that it was probably a conjugate of the aglycone digoxigenin. Digitoxin was excreted in only small amounts as the unchanged glycoside in this animal (4); the principal urinary product was a substance, Metabolite C, which was thought to be a conjugate of a derivative of digitoxigenin. With higher doses of digitoxin, other metabolites appeared in the urine, one of which was named Metabolite G. We have now been able to make a qualitative study of the cardioactive substances present in human urine after oral administration of digoxin, digitoxin, and lanatoside C and have compared the metabolites present with those found in rat urine. A preliminary communication (6) outlined evidence which indicated that hydroxylation occurred at C-12 in the digitoxin molecule in humans and in rats, thereby producing a urinary metabolite which could not be separated from the glycoside digoxin. This evidence was based on experiments in which paper chromatography and C14-digitoxin were used, and the details of this work are also presented in this paper.