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Concentrations of Gd-BOPTA in cholestatic fatty rat livers: role of transport functions through membrane proteins

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Published in Contrast Media & Molecular Imaging. 2013, vol. 8, no. 2, p. 147-56
Abstract Gd-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 resistance-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 on-line the hepatic concentrations of ¹⁵³Gd-BOPTA with a gamma probe placed over perfused rat livers. During the perfusion of ¹⁵³Gd-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 ¹⁵³Gd-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 ¹⁵³Gd-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 ¹⁵³Gd-BOPTA accumulates in hepatocytes is then complex. However, such understanding is important to analyze liver imaging with hepatobiliary contrast agents in cholestatic fatty livers.
Keywords AnimalsCholestasis, Intrahepatic/complications/metabolismComputer SimulationContrast Media/pharmacokineticsFatty Liver/complications/metabolismLiver/metabolismMeglumine/analogs & derivatives/pharmacokineticsMembrane Transport Proteins/metabolismMetabolic Clearance RateModels, BiologicalOrganometallic Compounds/pharmacokineticsRatsRats, ZuckerTissue Distribution
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PMID: 23281287
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Article (Published version) (750 Kb) - public document Free access
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Research groups Pharmacologie et imagerie du foie (664)
Neuroimagerie moléculaire en psychiatrie (983)
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PASTOR, Catherine, WISSMEYER, Michael, MILLET, Philippe. Concentrations of Gd-BOPTA in cholestatic fatty rat livers: role of transport functions through membrane proteins. In: Contrast Media & Molecular Imaging, 2013, vol. 8, n° 2, p. 147-56. https://archive-ouverte.unige.ch/unige:30830

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Deposited on : 2013-10-31

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