Assessment of DCEMRI with gadoxetate as a biomarker of drug induced cholestasis

INTRODUCTION One of the major patterns of drug-induced liver injury (DILI) observed in man is cholestatic DILI. The mechanisms are complex and include decreased bile formation, which results in increased bile acid levels in blood [1]. Hepatobiliary transporters mediate uptake and excretion of drugs and endogenous substances. It has been proposed that inhibition of biliary efflux transporters may play a key role in initiating cholestatic DILI [2]. Previously, we have shown that Dynamic Contrast Enhanced MRI (DCEMRI) with gadoxetate can be used as a suitable biomarker of transient cholestasic DILI caused by the well characterised cholestatic agent estradiol-β-D-glucuronide in the rat in vivo [3]. However, its utility for characterising cholestatic effects of investigational drugs has not yet been established. We have used an investigational chemokine agonist (CKA) as a model compound that caused cholestatic DILI in rats at high doses. The CKA compound inhibits the hepatobiliary efflux transporters Bsep and Mrp2 in vitro. It is not yet clear whether it is also a substrate and/or inhibitor of Oatp1 which mediates the uptake of gadoxetate [4]. The aim of the present study is to assess the sensitivity of DCEMRI as a potential biomarker of drug-induced cholestasis by exploring the dose-dependent relationship between the CKA model compound, gadoxetate uptake and efflux kinetics, and clinical chemistry markers of DILI.