Effects of CpG-DNA from Escherichia coli on digoxin pharmacokinetics.
Deoxyribonucleic acid (DNA) from bacteria or viruses has been reported as one of the pathogen-associated molecular patterns (PAMPs) and a substance that can induce endotoxemia-like inflammation in animals. However, there has been no report on digoxin pharmacokinetics in the inflammation induced by bacterial DNA containing unmethylated CpG motifs (CpG-DNA). In this study, we investigated the effects of CpG-DNA on digoxin pharmacokinetics. We determined the degree of lipopolysaccharide contamination in CpG-DNA solution and examined the changes in digoxin pharmacokinetics in rats after CpG-DNA administration. In addition, plasma concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and nitrite/nitrate (NOx) were determined after CpG-DNA administration (5 mg/kg, i.p.). The AUC0-24 of digoxin increased significantly on Day 1-3 and CL/F decreased on Day 1 and Day 2 after CpG-DNA administration. On Day 7 after CpG-DNA administration, there were no significant differences in AUC0-24 and CL/F compared with the control group (without CpG-DNA administration). However, Kel remained relatively unchanged throughout the experiment. Plasma TNF-alpha concentrations were significantly increased at 1 h and plasma IL-1beta concentrations were significantly decreased at 6 h after administration of CpG-DNA, while plasma NOx concentrations were significantly increased at 12 h after CpG-DNA administration, compared with the control group. These findings suggest that CpG-DNA (5 mg/kg) induces a transient inflammatory condition, and that AUC0-24 and CL/F of digoxin were altered after CpG-DNA administration. Digoxin pharmacokinetics recovered within 7 d after CpG-DNA exposure.
Kato
Ryuji
R
Laboratory of Clinical Pharmacy and Clinical Pharmacokinetics, Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki, Japan.
Tokunaga
Yuka
Y
Kawai
Takako
T
Tsukura
Yuri
Y
Amano
Fumio
F
Hirotani
Yoshihiko
Y
Ijiri
Yoshio
Y
Tanaka
Kazuhiko
K
D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002316:Cardiotonic Agents / Q000493:pharmacokinetics*; D018899:CpG Islands; D004269:DNA, Bacterial / Q000737:chemistry / Q000494:pharmacology*; D004077:Digoxin / Q000493:pharmacokinetics*; D004926:Escherichia coli / Q000737:chemistry*; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D002316:Cardiotonic Agents; D004269:DNA, Bacterial; D053583:Interleukin-1beta; D009566:Nitrates; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D004077:Digoxin