THE EFFECT OF ENDOTOXEMIA ON THE PHARMACOKINETICS OF DIGOXIN IN CONSCIOUS MALE RABBITS

Multiple organ failure (MOF) is induced by Escherichia coli lipopolysaccharide (LPS) alters the clearance of several drugs in experimental animals and human being. To give an insight about this phenomenon, the present study aimed to investigate single dose pharmacokinetics of digoxin in normal healthy male rabbits and LPS pretreated rabbits. Liver and kidney functions as well as their histopathological changes were studied to elucidate the probable mechanism(s) involved in this interaction.
Five groups of healthy male rabbits were used. The first group served as control. The second group received saline (LPS solvent) in marginal car vein A third group of rabbits received digoxin (0.02 mg/ ml/kg, p.o). The fourth group received LPS (800 µg/kg) in marginal car vein The fifth group received digoxin (0.02 mg/kg, p.o) eight hours after the intravenous injection of LPS( 800 µg/kg)
Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, blood urea nitrogen (BUN) and creatinine were determined. Serum nitric oxide was estimated by Griess reaction. To study the pharmacokinetic behavior of digoxin, blood was collected 025, 0.5, 1, 1.5,2,4,6,8, and12 hours after digoxin administration for determination of its serum level. Administration of digoxin or saline to rabbits had no significant effect on liver functions, kidney functions and serum nitric oxide levels On the other hand, a significant increase in kidney, liver functions and serum nitric oxide were observed in LPS alone or in combination with digoxin treated rabbits. In addition, a significant increase in the area under the serum digoxin concentration-time curve and increase in maximum concentration were observed in rabbits pretreated with lipopolysaccharide.
A brief word caution should be mentioned that in the acute period of Gram-negative bacterial infection, it is necessary to take into account the possibility of significant pharmacokinetic changes of some drugs, especially those having narrow therapeutic range as digoxin Therefore, digoxin serum level must be monitored carefully in endotoxemic patients, and the doses of digoxin may need readjustment in those patients