Risk Factors for Development of Cholestatic Drug-Induced Liver Injury: Inhibition of Hepatic Basolateral Bile Acid Transporters Multidrug Resistance-Associated Proteins 3 and 4

Kathleen Köck; Brian C. Ferslew; Ida Netterberg; Kyunghee Yang; Thomas J. Urban; Peter W. Swaan; Paul W. Stewart; Kim L. R. Brouwer

doi:10.1124/dmd.113.054304

Abstract

Impaired hepatic bile acid export may contribute to development of cholestatic drug-induced liver injury (DILI). The multidrug resistance-associated proteins (MRP) 3 and 4 are postulated to be compensatory hepatic basolateral bile acid efflux transporters when biliary excretion by the bile salt export pump (BSEP) is impaired. BSEP inhibition is a risk factor for cholestatic DILI. This study aimed to characterize the relationship between MRP3, MRP4, and BSEP inhibition and cholestatic potential of drugs. The inhibitory effect of 88 drugs (100 μM) on MRP3- and MRP4-mediated substrate transport was measured in membrane vesicles. Drugs selected for investigation included 50 BSEP non-inhibitors (24 non-cholestatic; 26 cholestatic) and 38 BSEP inhibitors (16 non-cholestatic; 22 cholestatic). MRP4 inhibition was associated with an increased risk of cholestatic potential among BSEP non-inhibitors. In this group, for each 1% increase in MRP4 inhibition, the odds of the drug being cholestatic increased by 3.1%. Using an inhibition cutoff of 21%, which predicted a 50% chance of cholestasis, 62% of cholestatic drugs inhibited MRP4 (P < 0.05); in contrast, only 17% of non-cholestatic drugs were MRP4 inhibitors. Among BSEP inhibitors, MRP4 inhibition did not provide additional predictive value of cholestatic potential; almost all BSEP inhibitors were also MRP4 inhibitors. Inclusion of pharmacokinetic predictor variables (e.g., maximal unbound concentration in plasma) in addition to percent MRP4 inhibition in logistic regression models did not improve cholestasis prediction. Association of cholestasis with percent MRP3 inhibition was not statistically significant, regardless of BSEP-inhibition status. Inhibition of MRP4, in addition to BSEP, may be a risk factor for the development of cholestatic DILI.

Footnotes

Received August 18, 2013.
Accepted October 23, 2013.

This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant R01 GM041935 to K.L.R.B. and a NIGMS Collaborative Science Supplement to K.L.R.B, T.J.U. and P.W.Sw.] and by Deutsche Forschungsgemeinschaft [Grant Ko4186/1-1 to K.K.]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
This work was presented, in part, as a poster at the Society of Toxicology 51st Annual Meeting; 2012 Mar 10–15; San Francisco, CA, and at the American Association for the Study of Liver Disease 63rd Annual Meeting; 2012 Nov 9–13; Boston, MA.
dx.doi.org/10.1124/dmd.113.054304.
This article has supplemental materials available at dmd.aspetjournals.org.