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

Georgiou, Leonidas PhD*†; Penny, Jeffrey PhD; Nicholls, Glynis PhD§; Woodhouse, Neil DCR, PhD; Blé, François-Xavier PhD; Naish, Josephine H. PhD*; Hubbard Cristinacce, Penny L. PhD*

doi: 10.1097/RLI.0000000000000480
Original Articles
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Objectives 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.

Materials and Methods 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.

Results 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 space, vecs) adequately described the observed liver concentration time series with mean ki = 0.47 ± 0.11 min−1 and mean kef = 0.039 ± 0.016 min−1. Visually, the area under the liver concentration time profile was reduced for the groups receiving rifampicin. Furthermore, tracer kinetic modeling demonstrated a significant dose-dependent decrease in the uptake (5.9- and 17.3-fold decrease for 20 mg/kg and 40 mg/kg, respectively) and efflux rates (2.2- and 7.9-fold decrease) compared with the first scan for each group.

Conclusions This study presents the first in vivo implementation of a 2-compartment uptake and efflux model to monitor DDIs at the transporter-protein level, using the clinically relevant organic anion transporting polypeptide inhibitor rifampicin. The technique has the potential to be a novel alternative to other methods, allowing real-time changes in transporter DDIs to be measured directly in vivo.

From the *Centre for Imaging Sciences, University of Manchester, Manchester, United Kingdom;

Department of Medical Physics, German Oncology Center, Limassol, Cyprus;

Manchester Pharmacy School, University of Manchester, Manchester;

§Drug Safety and Metabolism, and

Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom.

Received for publication January 31, 2018; and accepted for publication, after revision, March 31, 2018.

Conflicts of interest and sources of funding: The study was funded by a BBSRC and AstraZeneca CASE award. The authors declare no conflict of interest.

Correspondence to: Penny L. Hubbard Cristinacce, PhD, Centre for Imaging Sciences, University of Manchester, Stopford Bldg, Oxford Rd, Manchester, M13 9PT, United Kingdom. E-mail: penny.cristinacce@manchester.ac.uk.

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