Expression of Drug Pump Protein MRP2 in Lipopolysaccharide-Treated Rats and Its Impact on the Disposition of Acetaminophen

Abstract

The drug pump protein MRP2 is a membrane drug efflux transporter widely distributed in normal and tumor tissues. Its role is thought to be crucial for the disposition of many drugs and their substrates in different tissues. In this study, we aimed to examine the effects of systematic inflammation induced by lipopolysaccharide (LPS) on the expression and function of this transporter in rats. Jugular cannulated rats were injected intraperitoneally with LPS. Control rats received equal volume of sterile saline buffer. Rat liver MRP2 expression was analyzed at the level of mRNA through reverse transcription polymerase chain reaction. At various time points following drug administration (15 to 360 min), 250 µL blood samples were obtained from the cannula. The plasma was separated by centrifugation and stored at -20°C until HPLC analysis. Administration of LPS resulted in a slight but not significant increase in MRP2 mRNA levels 24 h after the treatment. In HPLC analysis, a rapid decrease in plasma concentrations of the MRP2 substrate (APAP) was observed at the initial time points. At later time points, the slope of the substrate concentration reached a plateau and paralleled to those of controls. It was postulated that due to the presence of the possible compensatory transport mechanisms in liver and non-hepatic tissues, changes performed to the pump activity were not completely in parallel to the expression of the drug efflux pump.