Quantification of drug transport function across the multiple resistance-associated protein 2 (Mrp2) in rat livers.

Abstract

To understand the transport function of drugs across the canalicular membrane of hepatocytes, it would be important to measure concentrations in hepatocytes and bile. However, these concentration gradients are rarely provided. The aim of the study is then to measure these concentrations and define parameters to quantify the canalicular transport of drugs through the multiple resistance associated-protein 2 (Mrp2) in entire rat livers. Besides drug bile excretion rates, we measured additional parameters to better define transport function across Mrp2: (1) Concentration gradients between hepatocyte and bile concentrations over time; and (2) a unique parameter (canalicular concentration ratio) that represents the slope of the non-linear regression curve between hepatocyte and bile concentrations. This information was obtained in isolated rat livers perfused with gadobenate dimeglumine (BOPTA) and mebrofenin (MEB), two hepatobiliary drugs used in clinical liver imaging. Interestingly, despite different transport characteristics including excretion rates into bile and hepatocyte clearance into bile, BOPTA and MEB have a similar canalicular concentration ratio. In contrast, the ratio was null when BOPTA was not excreted in bile in hepatocytes lacking Mrp2. The canalicular concentration ratio is more informative than bile excretion rates because it is independent of time, bile flows, and concentrations perfused in portal veins. It would be interesting to apply such information in human liver imaging where hepatobiliary compounds are increasingly investigated.