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

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

Effects of monensin sodium on digoxin kinetics in conscious male rabbits

The investigation was performed on male rabbits equally divided into two groups: digoxin treated group and monensin plus digoxin treated group. Digoxin [0.2 mg/kg] was administered orally as a single dose to normal and monensin [6mg/kg for three successive days] pretreated rabbits. Blood samples were obtained at 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0 and 12.0 hr. after digoxin administration. Pharmacokinetic parameters of digoxin were indicated by determination of area under the curve from time 0 to time t [AUC[t]], the area under the curve from time zero to infinity[AUC[alpha]], the half-life of the drug [t[1/2]], time required to reach maximum drug concentration[t[max]], maximum drug concentration in the blood [C[max]], drug clearance [C1] and the area under first moment curve [AUMC]. A significant increase in area under the serum concentration -time curve [AUC], increase in maximum concentration [C[max]], and area under moment curve [AUMC] were observed. In addition, Digoxin clearance [C1] was significantly reduced in rabbits pretreated with monensin. While, half-life [t[1/2]] and time required to reach maximum concentration [t[max]] was non significantly changed. The current results suggest that monensin enhance the adverse effects of digoxin in male rabbits. This interaction is played at least in part through an increase of digoxin plasma levels