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1.
Innate Immun ; 14(5): 291-7, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18809653

ABSTRACT

It has been reported that infection interferes with drug metabolism, resulting in changes in pharmacokinetics. In this study, we investigated the effects of lipopolysaccharide (LPS) on hepatic total cytochrome P450 (CYP), CYP3A2, and CYP2C11 contents in a transient, LPS-induced, endotoxemia model of rats. In addition, to assess the effects on CYP3A2 activities, the pharmacokinetics of midazolam (CYP3A2 substrate) and 1-OH-midazolam (metabolite of midazolam) were investigated. Hepatic total CYP contents were significantly low until day 3 (P < 0.05) but returned to the control level on day 5. Hepatic CYP3A2 contents were significantly decreased on day 1 until day 5 (P < 0.05) but returned to the control level on day 7. Hepatic CYP2C11 contents were continuously low until day 7, and lowest on day 3. The AUC of 1-OH-midazolam was significantly decreased on day 1 after LPS administration (P < 0.01). In conclusion, LPS (5 mg/kg) challenge decreased hepatic total CYP, CYP3A2, and CYP2C11 contents and also decreased the activities of hepatic CYP3A2. It took at least 7 days for hepatic total CYP and CYP3A2 to recover to control levels, and it was suggested that the changes of hepatic total CYP contents might correlate with those of hepatic CYP3A2 contents and activities. Additionally, it is shown that their changes might reflect the recovery process from inflammation.


Subject(s)
Aryl Hydrocarbon Hydroxylases/metabolism , Cytochrome P-450 Enzyme System/analysis , Endotoxemia/metabolism , Lipopolysaccharides/immunology , Membrane Proteins/metabolism , Midazolam/pharmacokinetics , Steroid 16-alpha-Hydroxylase/metabolism , Animals , Aryl Hydrocarbon Hydroxylases/analysis , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/drug effects , Cytochrome P450 Family 2 , Disease Models, Animal , Endotoxemia/blood , Endotoxemia/immunology , Interleukin-1beta/blood , Liver/enzymology , Liver/immunology , Male , Membrane Proteins/analysis , Midazolam/blood , Nitric Oxide/blood , Rats , Rats, Wistar , Steroid 16-alpha-Hydroxylase/analysis , Tumor Necrosis Factor-alpha/blood
2.
Biol Pharm Bull ; 31(6): 1221-5, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18520058

ABSTRACT

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.


Subject(s)
Cardiotonic Agents/pharmacokinetics , Digoxin/pharmacokinetics , Lipopolysaccharides/pharmacology , Administration, Oral , Algorithms , Animals , Area Under Curve , Blood Pressure/drug effects , Body Temperature/drug effects , Cardiotonic Agents/administration & dosage , Cytokines/blood , Digoxin/administration & dosage , Endotoxemia/chemically induced , Endotoxemia/metabolism , Escherichia coli/chemistry , In Vitro Techniques , Injections, Intravenous , Interleukin-1beta/blood , Intestinal Absorption , Intestinal Mucosa/metabolism , Male , Rats , Rats, Wistar , Tumor Necrosis Factor-alpha/metabolism
3.
Biol Pharm Bull ; 31(6): 1226-9, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18520059

ABSTRACT

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.


Subject(s)
Cardiotonic Agents/pharmacokinetics , DNA, Bacterial/pharmacology , Digoxin/pharmacokinetics , Escherichia coli/chemistry , Animals , Area Under Curve , Biological Availability , CpG Islands , DNA, Bacterial/chemistry , Interleukin-1beta/metabolism , Male , Nitrates/blood , Nitrites/blood , Rats , Rats, Wistar , Tumor Necrosis Factor-alpha/metabolism
4.
Biol Pharm Bull ; 30(10): 1982-6, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17917278

ABSTRACT

Recent studies suggest that capsaicin (Cap), a major constituent of hot pepper, may affect the function and permeability of the intestinal mucosa in vitro. However, the relationships between the dose of Cap and the barrier and/or transporter functions on intestinal epithelial cells are unknown. The aim of this study was to investigate whether Cap initiates cellular injury and alter epithelial permeability in Caco-2 cells. Cellular toxicity, as measured using a lactate dehydrogenase release assay, was not observed at high concentrations of Cap (up to 300 microM). When cell viability was measured by a WST-1 assay (tetrazolium salt-based assay), damage to Caco-2 monolayers was observed at doses of 200 and 300 microM of Cap. The barrier function of tight junctions was assessed by measuring transepithelial electrical resistance (TEER) in Caco-2 cells. Treatment of Caco-2 cells with Cap at doses above 100 microM significantly decreased the TEER compared to treatment with buffer alone for 2 h (p<0.05). We next examined the effects of Cap on the activity of P-glycoprotein (P-gp) found on transcellular transporters. At doses of 100 and 200 microM, Cap inhibited the transport of rhodamine 123 by P-gp-mediated efflux in Caco-2 cells. Cap thus exhibited inhibitory effects on P-gp. The results of this study indicate that Cap, a dietary phytochemical, causes functional and structural changes in Caco-2 cell monolayers at noncytotoxic doses (less than 100 microM of Cap). The concomitant administration of Cap with drugs that are substrates of P-gp might increase the plasma concentrations of such drugs.


Subject(s)
Capsaicin/pharmacology , Cell Membrane Permeability/drug effects , Cell Membrane/drug effects , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Caco-2 Cells , Cell Membrane/ultrastructure , Cell Survival/drug effects , Coloring Agents , Data Interpretation, Statistical , Electric Impedance , Enterocytes/drug effects , Humans , Intestinal Absorption/drug effects , Intestinal Mucosa/cytology , Intestinal Mucosa/drug effects , L-Lactate Dehydrogenase/metabolism , Pharmaceutical Preparations/metabolism , Rhodamine 123 , Tetrazolium Salts , Tight Junctions/drug effects
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