RT Journal Article SR Electronic T1 Gene-by-Environment Interaction of Bcrp−/− and Methionine- and Choline-Deficient Diet–Induced Nonalcoholic Steatohepatitis Alters SN-38 Disposition JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1478 OP 1486 DO 10.1124/dmd.118.082081 VO 46 IS 11 A1 Erica L. Toth A1 Hui Li A1 Anika L. Dzierlenga A1 John D. Clarke A1 Anna Vildhede A1 Michael Goedken A1 Nathan J. Cherrington YR 2018 UL http://dmd.aspetjournals.org/content/46/11/1478.abstract AB Disease progression to nonalcoholic steatohepatitis (NASH) has profound effects on the expression and function of drug-metabolizing enzymes and transporters, which provide a mechanistic basis for variable drug response. Breast cancer resistance protein (BCRP), a biliary efflux transporter, exhibits increased liver mRNA expression in NASH patients and preclinical NASH models, but the impact on function is unknown. It was shown that the transport capacity of multidrug resistance protein 2 (MRP2) is decreased in NASH. SN-38, the active irinotecan metabolite, is reported to be a substrate for Bcrp, whereas SN-38 glucuronide (SN-38G) is a Mrp2 substrate. The purpose of this study was to determine the function of Bcrp in NASH through alterations in the disposition of SN-38 and SN-38G in a Bcrp knockout (Bcrp−/− KO) and methionine- and choline-deficient (MCD) model of NASH. Sprague Dawley [wild-type (WT)] rats and Bcrp−/− rats were fed either a methionine- and choline-sufficient (control) or MCD diet for 8 weeks to induce NASH. SN-38 (10 mg/kg) was administered i.v., and blood and bile were collected for quantification by liquid chromatography–tandem mass spectrometry. In Bcrp−/− rats on the MCD diet, biliary efflux of SN-38 decreased to 31.9%, and efflux of SN-38G decreased to 38.7% of control, but WT-MCD and KO-Control were unaffected. These data indicate that Bcrp is not solely responsible for SN-38 biliary efflux, but rather implicate a combined role for BCRP and MRP2. Furthermore, the disposition of SN-38 and SN-38G is altered by Bcrp−/− and NASH in a gene-by-environment interaction and may result in variable drug response to irinotecan therapy in polymorphic patients.