RESUMO
Infection and inflammation suppress the expression and activity of several drug transporters in the liver. In the intestine, P-glycoprotein (PGP/mdr1) and the multidrug resistance-associated protein 2 (MRP2) are important barriers to the absorption of many clinically important drugs. The protein expression and activity of these transporters were examined during inflammation induced by lipopolysaccharide (LPS). The transport of rhodamine123 (Rho123) and 5-carboxyfluorescein (5-CF) was determined in isolated ileal segments from endotoxin-treated or control rats in the presence or absence of inhibitors. The reverse transcription-polymerase chain reaction was used to measure mRNA levels. Compared with the controls, the mRNA levels of mdr1a and mrp2 were significantly decreased by approximately 50% in the ilea of the LPS-treated rats. Corresponding reductions in the basolateral-apical efflux of Rho123 and 5-CF were observed, resulting in significant increases in the apical-basolateral absorption of these compounds. Neither the permeability of fluorescein isothiocyanate labeled dextran 4000 (FD-4), a paracellular marker, nor membrane resistance was altered. These results indicate that endotoxin-induced inflammation reduces the intestinal expression and activity of PGP and MRP2 in rats, which eliciting corresponding changes in the intestinal transport of their substrates. Hence, infection and inflammatory diseases may induce variability in drug bioavailability through alterations in the intestinal expression and activity of drug transporters.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Endotoxinas/farmacologia , Íleo/efeitos dos fármacos , Íleo/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Resistência a Múltiplos Medicamentos , Fluoresceínas/farmacocinética , Expressão Gênica/efeitos dos fármacos , Infecções/genética , Infecções/metabolismo , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Proteínas de Membrana Transportadoras/genética , RNA Mensageiro/genética , Ratos , Ratos Wistar , Rodamina 123/farmacocinéticaRESUMO
The effects of lipopolysaccharide (LPS) on the ileal and biliary excretion of rhodamine123 were investigated in rats at different times after intraperitoneal (i.p.) injection (1 mg/kg and 5 mg/kg of body weight). P-gp protein decreased 8h after injection of LPS and returned to the control level 24h after i.p. injection of LPS in the ileum. There was a marked decrease in the expression level of mdr1a mRNA in the ileum and liver 8h after i.p. injection of LPS when compared with the control condition. Also, the ileal and biliary clearance of rhodamine123 significantly decreased 8h after i.p. injection of LPS, but returned to the control levels 24h after i.p. injection of LPS. These results suggest that LPS-induced decreases in P-gp-mediated ileal and biliary excretion of rhodamine123 were probably due to impaired P-gp-mediated transport ability. The levels of iNOS and IL-1beta mRNA in the ileum and liver increased 2 and 8h after i.p. injection of LPS, respectively, and returned to the control levels 24h after injection of LPS. These findings suggest that LPS markedly decreases P-gp-mediated ileal and biliary excretion of rhodamine123, probably by partly decreasing the expression of P-gp protein levels, likely due to increased lipid peroxidation levels through iNOS mRNA and inflammatory mediators such as IL-1beta.
