Modeling Gadoxetate Liver Uptake and Efflux Using Dynamic Contrast-Enhanced Magnetic Resonance Imaging Enables Preclinical Quantification of Transporter Drug-Drug Interactions

Investigative Radiology
Leonidas GeorgiouPenny L Hubbard Cristinacce

Abstract

The aim of this study was to model the in vivo transporter-mediated uptake and efflux of the hepatobiliary contrast agent gadoxetate in the liver. The efficacy of the proposed technique was assessed for its ability to provide quantitative insights into drug-drug interactions (DDIs), using rifampicin as inhibitor. Three groups of C57 mice were scanned twice with a dynamic gadoxetate-enhanced magnetic resonance imaging protocol, using a 3-dimensional spoiled gradient-echo sequence for approximately 72 minutes. Before the second magnetic resonance imaging session, 2 of the groups received a rifampicin dose of 20 (n = 7) or 40 (n = 7) mg/kg, respectively. Data from regions of interest in the liver were analyzed using 2 simplifications of a 2-compartment uptake and efflux model to provide estimates for the gadoxetate uptake rate (ki) into the hepatocytes and its efflux rate (kef) into the bile. Both models were assessed for goodness-of-fit in the group without rifampicin (n = 9), and the appropriate model was selected for assessing the ability to monitor DDIs in vivo. Seven of 9 mice from the group without rifampicin were assessed for model implementation and reproducibility. A simple 3 parameter model (ki, kef, and extracellular sp...Continue Reading

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Citations

Jan 18, 2020·Expert Opinion on Drug Metabolism & Toxicology·Irene Hernández Lozano, Oliver Langer

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