Mechanism of expression and function of drug transporters in endotoxemia

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Firstly, the effect of endotoxin (ET) on the function and expression of hepatic breast cancer resistance protein (Bcrp) was investigated in mice. In vivo clearance experiments showed that the biliary clearance (CL_<BILE>) of mitoxantrone was significantly decreased 24 h after ET injection. Both Western blot and immunofluorescence analyses also revealed that the protein levels of hepatic Bcrp were decreased 24 h after injection of ET. ET significantly induced the overproduction of the cytokines IL-6 and IL-1β. Pretreatment with IL-6 significantly decreased the CL_<BILE> of mitoxantrone. Hepatic Bcrp was significantly down-regulated by injection of IL-6 (50,000U/mouse). These findings suggest that ET reduces Bcrp-mediated hepatobiliary excretion of mitoxantrone by decreasing the expression of hepatic Bcrp, which is likely due to increased IL-6 levels. Secondly, to clarify ET-induced changes in organic anion transport ability, GFR and renal tubular secretion clearance of PAH which is a substrate for renal organic anion transporter 1 (Oat1) and Oat3 were investigated in endotoxemic rats. The expression of Oat1 and Oat3 mRNA was decreased, and the expression returned to control levels after 72 h after injection of ET. These findings suggest that the decreased mRNA levels of renal Oat1 and Oat3 are involved in the decreased renal tubular secretion clearance of PAH in endotoxemic rats and that these changes are transient and recovered time-dependently.