In the liver, the accumulation of hepatobiliary contrast agents is a crucial issue to understand the images of liver scintigraphy or magnetic resonance - MR - imaging. Thus, depending on the regulation of uptake and exit membrane systems in normal and injured hepatocytes, these contrast agents will differently accumulate within cells. Gd-BOPTA is a hepatobiliary MR contrast agent that distributes to the extracellular space and enters into rat hepatocytes through the sinusoidal transporters Oatps. Gd-BOPTA is not metabolized during its transport to the canalicular membrane where it is excreted into bile through Mrp2. It is incompletely known how Gd-BOPTA accumulates in normal livers and in livers lacking Mrp2. We then perfused livers from normal rats and rats lacking Mrp2 with 153Gd-BOPTA at increasing concentrations and assessed the hepatic accumulation of this agent using a gamma probe placed above the livers. Using a pharmacokinetic model that best described the amounts of Gd-BOPTA in perfusate, bile, and hepatic tissue over time, we showed how increasing concentrations and the absence of Mrp2 modify the hepatic accumulation of the contrast agent. Interestingly, despite the absence of Gd-BOPTA bile excretion and a similar efflux back to sinusoids in livers lacking Mrp2, the maximal hepatic accumulation of contrast agent was similar to normal rats. We also showed how hepatic accumulation relies on the concomitant entry into and exit from hepatocytes. Such information improves our understanding of liver imaging associated with the perfusion of hepatobiliary contrast agents, which was recently introduced in clinical practice.
- Received September 27, 2010.
- Revision received December 1, 2010.
- Accepted December 1, 2010.
- The American Society for Pharmacology and Experimental Therapeutics