Changes in digoxin pharmacokinetics treated with lipopolysaccharide in Wistar rats.
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 AUCi.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 AUCp.o. was significantly increased in the LPS (+) group (p<0.05). The AUCloop 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.
Laboratory of Clinical Pharmacy and Clinical Pharmacokinetics, Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki, Japan.
Ryuji
R
Kato
Azusa
A
Fujiwara
Takako
T
Kawai
Jun
J
Moriguchi
Machiko
M
Nakagawa
Yuri
Y
Tsukura
Kagehiro
K
Uchida
Fumio
F
Amano
Yoshihiko
Y
Hirotani
Yoshio
Y
Ijiri
Kazuhiko
K
Tanaka
D000284:Administration, Oral; D000465:Algorithms; D000818:Animals; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016207:Cytokines / Q000097:blood; D004077:Digoxin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019446:Endotoxemia / Q000139:chemically induced / Q000378:metabolism; D004926:Escherichia coli / Q000737:chemistry; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D053583:Interleukin-1beta / Q000097:blood; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D002316:Cardiotonic Agents; D016207:Cytokines; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D004077:Digoxin