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A multi-center preclinical study of gadoxetate DCE-MRI in rats as a biomarker of drug induced inhibition of liver transporter function.
Safety and ADME Translational Sciences, Drug Safety and Metabolism, AstraZeneca, Gothenburg, Sweden..
Bioimaging, Platform Technology and Sciences, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America..
Research Imaging Sciences, Amgen, Thousand Oaks, California, United States of America..
Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Wolfram MathCore, Linköping, Sweden.ORCID iD: 0000-0003-4630-6550
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2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 5, article id e0197213Article in journal (Refereed) Published
Abstract [en]

Drug-induced liver injury (DILI) is a leading cause of acute liver failure and transplantation. DILI can be the result of impaired hepatobiliary transporters, with altered bile formation, flow, and subsequent cholestasis. We used gadoxetate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), combined with pharmacokinetic modelling, to measure hepatobiliary transporter function in vivo in rats. The sensitivity and robustness of the method was tested by evaluating the effect of a clinical dose of the antibiotic rifampicin in four different preclinical imaging centers. The mean gadoxetate uptake rate constant for the vehicle groups at all centers was 39.3 +/- 3.4 s-1 (n = 23) and 11.7 +/- 1.3 s-1 (n = 20) for the rifampicin groups. The mean gadoxetate efflux rate constant for the vehicle groups was 1.53 +/- 0.08 s-1 (n = 23) and for the rifampicin treated groups was 0.94 +/- 0.08 s-1 (n = 20). Both the uptake and excretion transporters of gadoxetate were statistically significantly inhibited by the clinical dose of rifampicin at all centers and the size of this treatment group effect was consistent across the centers. Gadoxetate is a clinically approved MRI contrast agent, so this method is readily transferable to the clinic.less thanbr /greater thanConclusion: Rate constants of gadoxetate uptake and excretion are sensitive and robust biomarkers to detect early changes in hepatobiliary transporter function in vivo in rats prior to established biomarkers of liver toxicity.

Place, publisher, year, edition, pages
Public Library of Science , 2018. Vol. 13, no 5, article id e0197213
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
URN: urn:nbn:se:liu:diva-148072DOI: 10.1371/journal.pone.0197213ISI: 000432348900035PubMedID: 29771932OAI: oai:DiVA.org:liu-148072DiVA, id: diva2:1210963
Note

Funding agencies: HESI; National Center for Toxicological Research (NCTR)/U.S. Food and Drug Administration (FDA) [P00800]; National Institutes of Health from the National Institute of General Medical Sciences [R01 GM041935, R35 GM122576]

Available from: 2018-05-30 Created: 2018-05-30 Last updated: 2019-11-11

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