Species differences in plasma binding and tissue uptake of 3H-digitoxin. A comparative study in rats and mice in vivo and in vitro.

The content of cardiac glycosides in plasma and several organs of rats and mice was investigated 30 min and 12 hrs after i.p. administration of 160 mug/kg b.w. 3H-digitoxin. In rat plasma a glycoside concentration of 124.8 and 44.7 ng/ml resp. was found. The corresponding values in the liver were 834.7 and 579.7 ng/g w.w. An opposite liver/plasma distribution was obtained in mice: while in plasma 772.5 and 571.8 ng/ml were recovered, the glycoside concentration in liver was relatively small (284.8 and 235.6 ng/g w.w.). In order to find out the reason for such species differences observed in vivo, liver slices of rats and mice were incubated with 3H-digitoxin in a medium with and without various plasma proteins. The uptake of 3H-digitoxin into liver slices was drastically reduced by adding mouse plasma or albumin to the medium, while rat plasma lowered the uptake far less. These differences are well reflected by binding studies on agargel electrophoresis: only in mouse plasma a binding of 3H-digitoxin could be demonstrated. The binding rate and binding constant analyzed by equilibrium dialysis were higher in mouse than in rat plasma. It is concluded that the lower tissue accumulation in mice compared to rats must be due to the affinity of 3H-digitoxin to mouse plasma albumin. Moreover digitoxin has a higher affinity to the rat than to the mouse liver in the presence of mouse or rat plasma as well as of bovine serum albumin.