Effect of total parenteral nutrition on the pharmacokinetics of digoxin and phenytoin in male rabbits

ABSTRACT

Total parenteral nutrition [TPN] is a therapeutic intervention designed to provide sufficient calories and nitrogen to sustain patients who are unable to consume adequate nourishment by mouth and are therefore at risk of developing malnutrition. Unfortunately, alterations in both hepatic and intestinal function accompany therapy with TPN. TPN depresses both hepatic oxidative and conjugative biotransformation, consequently, the metabolism and elimination rate of drugs may be affected. To give insight about this situation, the present study was designed to investigate the effect of total parenteral nutrition on single dose pharmacokinetics of digoxin and phenytoin in male rabbits. Thirty six rabbits were divided into six groups as follow the first three groups[I,II and III] were fed dry food and water, and the other three groups [IV, V and VI] received a total parenteral nutrition for ten days. Each group received a single IV dose of one drug as follow group I and IV received digoxin [0.02 mg/kg,iv], group II and V received phenytoin [10 mg/ kg, iv],and group III and VI received midazolam [1 mg/kg, iv]. Serum alanine aminotrasnferase [ALT], aspartate aminotransferase [AST] and total bilirubin were determined. Plasma nitric oxide was estimated by Griess reaction. Sleeping time induced by midazolam was recorded. To study the pharrnacokinetic behaviour of digoxin or phenytoin, blood was collected 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0 and /or 24.0 hours after digoxin or phenytoin administration for determination of their blood levels. Total parenteral nutrition induced a significant increase in liver functions, plasma nitric oxide levels, and sleeping time of midazolam. In addition, Total parenteral nutrition induced a significant increase in the area under plasma digoxin or phenytoin concentration-time curves [AUC]and half life [t 1/2] of both drugs. Moreover, TPN induced a significant decrease in the clearance rate [Cl] for both drugs. The present study revealed that, in case of TPN,it is necessary to take in consideration the possibility of significant pharmacokinetic changes of some drugs, especially those having a narrow therapeutic index as digoxin and phenytoin. Therefore. digoxin and phenytoin blood levels must be monitored carefully in patients under TPN, and the doses of digoxin and phenytoin may need readjustment in those patients