The uptake and subcellular distribution of radio-labeled metabolites of digoxin in the isolated perfused guinea-pig heart

Summary Cardiac glycosides like digitoxin and digoxin with three digitoxoside sugar residues have been reported to undergo step-wise degradation to yield the corresponding genins, and the importance of the digitoxoside side-chain for the pharmacodynamic property of cardiac glycosides has also been suggested. A systematic study was therefore undertaken on the cleavage products of digoxin. Digoxigenin-bis-digitoxoside (with two sugar residues) digoxigenin-monodigitoxoside (with one sugar residue) and digoxigenin (with no sugar) were compared with the parent compound, digoxin. The radio-labeled compounds were perfused through isolated guinea pig hearts using 10^–7 M concentration in the perfusion medium for a fixed period of 64 min followed by an 8 min period of wash-out with normal medium. The uptake and sub-cellular distribution of the drugs were thereafter measured by scintillation counting. All the compounds produced positive inotropic responses, the monodigitoxoside producing the greatest effect, digoxigenin next in order of inotropic response magnitude, the bis-digitoxoside produced the least effect, and digoxin was intermediate between the genin and bis-digitoxoside. The uptake of the monodigitoxoside was the highest, and in general, the quantitative uptake was related to the inotropic response. The greatest binding of each digitoxoside was found in the microsomal fraction. Both mechanical activity and uptake of all four drugs were uniformly reduced by an increase in potassium concentration in the perfusion medium.Supported by grant HE-07051 from the National Heart Institute