Assessment of gadoxetate DCE-MRI as a biomarker of hepatobiliary transporter inhibition
Journal article, 2013

Drug-induced liver injury (DILI) is a clinically important adverse drug reaction, which prevents the development of many otherwise safe and effective new drugs. Currently, there is a lack of sensitive and specific biomarkers that can be used to predict, assess and manage this toxicity. The aim of this work was to evaluate gadoxetate-enhanced MRI as a potential novel biomarker of hepatobiliary transporter inhibition in the rat. Initially, the volume fraction of extracellular space in the liver was determined using gadopentetate to enable an estimation of the gadoxetate concentration in hepatocytes. Using this information, a compartmental model was developed to characterise the pharmacokinetics of hepatic uptake and biliary excretion of gadoxetate. Subsequently, we explored the impact of an investigational hepatobiliary transporter inhibitor on the parameters of the model in vivo in rats. The investigational hepatobiliary transporter inhibitor reduced both the rate of uptake of gadoxetate into the hepatocyte, k 1 , and the Michaelis-Menten constant, V max , characterising its excretion into bile, whereas K M values for biliary efflux were increased. These effects were dose dependent and correlated with effects on plasma chemistry markers of liver dysfunction, in particular bilirubin and bile acids. These results indicate that gadoxetate-enhanced MRI provides a novel functional biomarker of inhibition of transporter-mediated hepatic uptake and clearance in the rat. Since gadoxetate is used clinically, the technology has the potential to provide a translatable biomarker of drug-induced perturbation of hepatic transporters that may also be useful in humans to explore deleterious functional alterations caused by transporter inhibition. © 2013 John Wiley & Sons, Ltd.

Hepatobiliary transporters

Pharmacokinetic model

DCE-MRI

Drug-induced liver injury

Liver

Imaging biomarker

Safety biomarker

DILI

Author

Jose L Ulloa

AstraZeneca AB

Simone Stahl

AstraZeneca AB

James Yates

AstraZeneca AB

Neil Woodhouse

AstraZeneca AB

J. Gerry Kenna

AstraZeneca AB

Huw B Jones

AstraZeneca AB

John C. Waterton

AstraZeneca AB

Paul Hockings

AstraZeneca AB

Electrical Engineering

NMR in Biomedicine

0952-3480 (ISSN) 1099-1492 (eISSN)

Vol. 26 10 1258-1270

Subject Categories

Pharmaceutical Sciences

Pharmacology and Toxicology

Radiology, Nuclear Medicine and Medical Imaging

DOI

10.1002/nbm.2946

PubMed

23564602

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Latest update

8/15/2024