RESUMO
In the present study, we investigated the influence of Cap on digoxin pharmacokinetics in lipopolysaccharide (LPS)-treated rats. After the oral administration of digoxin (0.1 mg/kg), the area under the plasma concentration-time curve (AUC) of digoxin increased significantly until day 3 after LPS treatment. In the LPS + Cap group, the recovery period of AUC was shortened to 3 days. On days 5 and 7, the maximum plasma concentrations decreased significantly as compared to the control group. The bioavailability of digoxin in LPS group was higher than that in the LPS + Cap group. The hepatic cytochrome P450 (CYP) 3A2 content decreased significantly until day 5 after LPS administration, but it returned to the control level until 5 days in the LPS + Cap group. Hepatic CYP3A2 mRNA expression of LPS group decreased significantly until day 3, but it returned to the control level on day 3 and increased significantly until day 7 in the LPS + Cap group. The DNA-binding activity of pregnane X receptor (PXR) was increased on days 3-7 in the Cap and LPS + Cap group. Cap decreased the absorption of digoxin by inducing CYP3A2 mRNA expression via indirect activation of PXR in LPS-treated rats.
Assuntos
Capsaicina/farmacologia , Digoxina/farmacocinética , Lipopolissacarídeos/farmacologia , Administração Oral , Animais , Western Blotting , Capsaicina/administração & dosagem , Citocromo P-450 CYP3A , DNA/metabolismo , Digoxina/administração & dosagem , Ensaio de Desvio de Mobilidade Eletroforética , Regulação da Expressão Gênica/efeitos dos fármacos , Injeções Intravenosas , Lipopolissacarídeos/administração & dosagem , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Receptor de Pregnano X , Ligação Proteica/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Esteroides/metabolismoRESUMO
There have been many reports that P-glycoprotein expression and activity are altered during sepsis, but few of them have examined such changes over 72 h. In this study, we examined the effect of lipopolysaccharide (LPS, 5mg/kg, ip) on P-glycoprotein expression (Western blotting) and activity (rhodamine-123 (Rho123) pharmacokinetics) in liver and kidneys for 7 days. On day 1 after LPS administration, hepatic P-glycoprotein expression and activity significantly decreased. On day 3, hepatic P-glycoprotein expression significantly increased compared with the control group, while activity had returned to the control level. On day 7, hepatic P-glycoprotein expression returned to the control level. There were no significant changes in P-glycoprotein expression or activity in the kidneys after LPS administration. The amount of Rho123 excretion in urine remained unchanged with (4.2%) or without (4.0%) LPS administration, but the amount of Rho123 excretion in bile decreased from 2.0 to 0.7% with LPS administration. Our findings suggested that hepatic P-glycoprotein expression and activity decreased on day 1 but recovered within 3 days, but there were no significant differences in the kidneys after LPS administration. These results suggested that the change in P-glycoprotein activity might be due to change in P-glycoprotein expression in the liver rather than the kidneys.
