Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (E.L.T., H.L., A.L.D., N.J.C.); Pharmaceutical Sciences, Washington State University, Spokane, Washington (J.D.C.); Pharmacokinetics, Dynamics, and Metabolism, Medicine Design, Pfizer Worldwide Research and Development, Groton, Connecticut (A.V.); and Research Pathology Services, Rutgers University, Newark, New Jersey (M.G.).
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (E.L.T., H.L., A.L.D., N.J.C.); Pharmaceutical Sciences, Washington State University, Spokane, Washington (J.D.C.); Pharmacokinetics, Dynamics, and Metabolism, Medicine Design, Pfizer Worldwide Research and Development, Groton, Connecticut (A.V.); and Research Pathology Services, Rutgers University, Newark, New Jersey (M.G.)
Drug Metab Dispos. 2018 Nov;46(11):1478-1486. doi: 10.1124/dmd.118.082081. Epub 2018 Aug 30.
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 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.
非酒精性脂肪性肝炎（NASH）向进展会对药物代谢酶和转运体的表达和功能产生深远影响，为药物反应的可变性提供了机制基础。乳腺癌耐药蛋白（BCRP）是一种胆汁外排转运体，在 NASH 患者和临床前 NASH 模型中肝 mRNA 表达增加，但功能影响尚不清楚。有研究表明，多药耐药蛋白 2（MRP2）的转运能力在 NASH 中降低。伊立替康的活性代谢物 SN-38 据报道是 Bcrp 的底物，而 SN-38 葡萄糖醛酸（SN-38G）是 Mrp2 的底物。本研究旨在通过改变 Bcrp 在 knockout（Bcrp KO）和蛋氨酸和胆碱缺乏（MCD）NASH 模型中 SN-38 和 SN-38G 的处置来确定 Bcrp 在 NASH 中的作用。Sprague Dawley [野生型（WT）]大鼠和 Bcrp 大鼠分别用蛋氨酸和胆碱充足（对照）或 MCD 饮食喂养 8 周以诱导 NASH。静脉给予 SN-38（10mg/kg），并通过液相色谱-串联质谱法收集血液和胆汁进行定量。在 MCD 饮食的 Bcrp 大鼠中，SN-38 的胆汁外排减少到对照的 31.9%，SN-38G 的胆汁外排减少到对照的 38.7%，但 WT-MCD 和 KO-Control 不受影响。这些数据表明 Bcrp 并非 SN-38 胆汁外排的唯一原因，而是 BCRP 和 MRP2 的共同作用。此外，SN-38 和 SN-38G 的处置受 Bcrp 和 NASH 的影响，存在基因-环境相互作用，可能导致多态性患者对伊立替康治疗的药物反应存在差异。
