Disposition of Digitoxin and Digoxin in Experimental Cholestasis and Renal Failure

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(I) At present it is assumed that the digitalis glycosides mainly undergo biotransformation in the liver. However, since the metabolism of the glycosides in cases of liver damage has not yet sufficiently been studied, there remain many problems to be solved in the future. In attempt to clarify digitalis metabolism in cholestasis, the plasma digitoxin and digoxin concentrations of dogs given with a single intravenous administration were determined by radioimmunoassay under the following four groups; (1) surgically prepared biliary ligation,(2) fistula,(3) ligation after phenobarbital pretreatment, and (4) sham-operation. The plasma digitoxin concentrations in ligated dogs were significantly higher than those with either fistula or sham-operation. But the plasma digitoxin concentrations in ligated dogs with phenobarbital pretreatment were significantly lower than those with the group (2) and (4), while plasma digoxin concentrations did not differ significantly between the four groups. After intravenous tritium digitoxin administration, both the dichloromethane-extractable radioactivity in plasma and the total radioactivities in the heart revealed significantly higer levels in ligated dogs than the other three groups. Biliary ligation resulted in marked decrease in the activities of drug metabolizing enzymes. The highly sustained plasma levels of digitoxin in ligated dogs appeared to correlate with the reduction of these enzyme activities. However, digoxin was excreted easily through the kidney despite cholestasis only if the renal function was normal. These data strongly suggest that in clinical practice, digoxin should be the choice of digitalis in patients with cholestasis. (II) There is disagreement among investigators concerning digitoxin metabolism and elimination in patients with impaired renal function. In order to elucidate the influence of renal function on digitoxin metabolism, both the radioactivity of dichloromethane-extractable fraction in plasma and the total radioactivity in tissues were determined in dogs with experimental renal failure induced by either bilateral nephrectomy or ureter ligations after a single intravenous dose of tritium digitoxin. The plasma dichloromethane-extractable radioactivity was remained at the higher level significantly in the nephrectomized and ureter-ligated dogs than the control, and the total radioactivity in the heart and the liver was significantly higher in the nephrectomized dogs than the control, but not significantly higher in the ureter-ligated dogs. In contrast to both the heart and the liver, the total radioactivity of the kidney was lower in the ureter-ligated dogs than the control. Although there are some reports that the elimination of digitoxin is not significantly affected by renal impairment, since our data suggest that the kideny appeared to play a significant role in the elimination of digitoxin, caution should be used in clinical practice when digitoxin is administered to patients with impaired renal function.
Japan Society of Clinical Chemistryの論文

Disposition of Digitoxin and Digoxin in Experimental Cholestasis and Renal Failure

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