RT Journal Article
SR Electronic
T1 How Organic Anions Accumulate in Hepatocytes Lacking Mrp2: Evidence in Rat Liver
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 624
OP 632
DO 10.1124/jpet.110.175406
VO 336
IS 3
A1 Philippe Millet
A1 Marcelle Moulin
A1 Bruno Stieger
A1 Youssef Daali
A1 Catherine M. Pastor
YR 2011
UL http://jpet.aspetjournals.org/content/336/3/624.abstract
AB 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 accumulate differently within cells. Gadobenate dimeglumine (Gd-BOPTA) is a hepatobiliary MR contrast agent that distributes to the extracellular space and enters into rat hepatocytes through the sinusoidal transporters, organic anion-transporting polypeptides. Gd-BOPTA is not metabolized during its transport to the canalicular membrane where it is excreted into bile through multiple resistance protein-2 (Mrp2). It is not well known how Gd-BOPTA accumulates in normal livers and in livers lacking Mrp2. We perfused livers from normal rats and from 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. By use of 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. It is noteworthy that 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.