Molecular pharmacokinetic studies on changes in the expression and function of drug transporters in endotoxemia

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The effect of Klebsiella pneumoniae endotoxin on the function and expression of hepatic breast cancer resistance protein (BCRP) remains unknown. In the present study, we investigated the effect of K.pneumoniae endotoxin on the hepatobiliary excretion of mitoxantrone, a typical substrate of BCRP in mice at different times after intraperitoneal injection of endotoxin (10mg/kg of body weight). The biliary clearance of mitoxantrone significantly decreased by 40% and 70% 6 and 24 h after endotoxin injection, respectively. Both Western blot and immunofluorescence analyses revealed that BCRP expression decreased 6 and 24 h after injection of endotoxin, which were consistent with the results from in vivo experiments. These results suggest that endotoxin-induced decrease in BCRP-mediated hepatobiliary excretion is caused, in part, by down-regulation of hepatic BCRP expression. Endotoxin significantly induced the production of cytokines including interleukin-6 (IL-6) and IL-1β. Pretreatment with IL-1β did not decrease the hepatobiliary excretion of mitoxantrone and down-regulate hepatic BCRP expression. However, pretreatment with IL-6 significantly decreased the hepatobiliary excretion of mitoxantrone. Western blot and immunofluorescence analyses also revealed that pretreatment with IL-6 decreased the expression of BCRP, which is in line with in vivo experiments. These findings suggest that K.pneumoniae endotoxin decreases BCRP-mediated hepatobiliary excretion of mitoxantrone by decreasing the expression of hepatic BCRP, which is likely due to increased plasma IL-6 levels.