Changes in Digoxin Pharmacokinetics Treated with Lipopolysaccharide in Wistar Rats

抄録

Lipopolysaccharide (LPS) is a highly bioactive substance that can cause local as well as systemic damage to various organs of both humans and animals, even at very low doses. However, there are a few reports on drug pharmacokinetics during endotoxemia. In this study, we analyzed the pharmacokinetics of digoxin (a therapeutic agent for cardiac insufficiency) as a probe drug for a two-compartment model in a rat model of endotoxemia induced by LPS for 5 d. Digoxin was given to Wistar rats intravenously (i.v.), orally (p.o.), and intra-intestinally using an in situ closed-loop method (loop). The AUC_i.v. was significantly increased in the LPS (+) group throughout the experiment (p<0.05). There was significant decrease in V₂ (volume of distribution of tissue compartment) on Day 1—3 (p<0.05). On Day 1—2 after LPS administration, the AUC_p.o. was significantly increased in the LPS (+) group (p<0.05). The AUC_loop was significantly increased throughout the experiment (p<0.05). The elimination rate constant was unchanged. Thus LPS administration affected the absorption but not the excretion of digoxin. The findings of this study suggest that digoxin absorption increased and the volume of distribution of tissue compartment decreased after LPS administration (5 mg/kg, i.p.). It appears that digoxin pharmacokinetics recover over 3 d after LPS administration.