Concentrations of Gda??BOPTA in cholestatic fatty rat livers: role of transport functions through membrane proteins

摘要

Gda??BOPTA (gadobenate dimeglumine) is a magnetic resonance (MR) contrast agent that, after i.v. administration, distributes within the extracellular space, enters rat hepatocytes through the sinusoidal transporters organic anion transporting peptides (Oatps) and is excreted unchanged into bile through the multidrug resistancea??associated protein 2 (Mrp2). It is unclear how the hepatobiliary contrast agent would accumulate in cholestatic fatty livers from obese rats with bile flow impairment. Indeed, the expression of both Oatps and Mrp2 transporters is decreased in cholestatic hepatocytes. To assess this question, we measured ona??line the hepatic concentrations of 153Gda??BOPTA with a gamma probe placed over perfused rat livers. During the perfusion of 153Gda??BOPTA, we obtained a similar maximal hepatic concentration in normal and fatty livers despite the decreased expression and function of membrane transporters in fatty livers. By pharmacokinetic modeling and mathematical simulations, we show how changes of transport into and out of hepatocytes modify the concentrations of 153Gda??BOPTA within hepatocytes. Mathematical simulations help to understand how each parameter (entry into hepatocytes, bile excretion, or efflux back to sinusoids) interferes with the hepatic concentrations. The hepatic concentrations of 153Gda??BOPTA within hepatocytes rely on the entry into hepatocytes through the sinusoidal membrane and on two paths of exit, the efflux back to sinusoids and the elimination into bile. Understanding how 153Gda??BOPTA accumulates in hepatocytes is then complex. However, such understanding is important to analyze liver imaging with hepatobiliary contrast agents in cholestatic fatty livers. Copyright ?? 2012 John Wiley & Sons, Ltd.