title: Risk factors for development of cholestatic drug-induced liver injury: inhibition of hepatic basolateral bile acid transporters multidrug resistance-associated proteins 3 and 4.
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.
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy (K.K., B.C.F., I.N., K.Y., K.L.R.B.), and Biostatistics Department, School of Public Health (P.W.St.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Pharmacy, Uppsala University, Uppsala, Sweden (I.N.); Center for Human Genome Variation, Duke University Medical Center, Durham, North Carolina (T.J.U.); and Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland (P.W.Sw.).
authors.forename: Kathleen
authors.initials: K
authors.lastname: Köck
authors.forename: Brian C
authors.initials: BC
authors.lastname: Ferslew
authors.forename: Ida
authors.initials: I
authors.lastname: Netterberg
authors.forename: Kyunghee
authors.initials: K
authors.lastname: Yang
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Urban
authors.forename: Peter W
authors.initials: PW
authors.lastname: Swaan
authors.forename: Paul W
authors.initials: PW
authors.lastname: Stewart
authors.forename: Kim L R
authors.initials: KL
authors.lastname: Brouwer
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism*; D002779:Cholestasis / Q000139:chemically induced / Q000378:metabolism*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000209:etiology / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D016015:Logistic Models; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000737:chemistry; D011237:Predictive Value of Tests; D012307:Risk Factors; D014162:Transfection
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D004364:Pharmaceutical Preparations; C093491:ABCB11 protein, human; C073492:ABCC4 protein, human; C114462:multidrug resistance-associated protein 3