Gene-by-Environment Interaction of Bcrp−/− and Methionine- and Choline-Deficient Diet–Induced Nonalcoholic Steatohepatitis Alters SN-38 Disposition

Abstract

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.

A Pharmacokinetic Natural Product-Disease-Drug Interaction: A Double Hit of Silymarin and Nonalcoholic Steatohepatitis on Hepatic Transporters in a Rat Model

“…Fig. 4F) suggest that the previously reported increase in BCRP protein expression in NASH potentially plays a role in producing high pitavastatin biliary concentrations (Hardwick et al, 2011;Toth et al, 2018). The silymarin-mediated decrease in bile flow observed in the present study is inconsistent with a previous report showing that intraperitoneal administration of silymarin increased bile flow (Crocenzi et al, 2000).…”

Representative Rodent Models for Renal Transporter Alterations in Human Nonalcoholic Steatohepatitis

“…These alterations can cause a shift in the distribution and elimination profile of various xenobiotics resulting in a higher systemic concentration, prolonged plasma retention, and decreased biliary excretion (Hardwick et al, 2012;Hardwick et al, 2014;Clarke et al, 2015;Toth et al, 2018;Toth et al, 2020).…”

Non-alcoholic Steatohepatitis (NASH) Drug Discovery – Building a Consensus on ADME Screening Tools and Clinical Pharmacology Strategies to Aid Candidate Development

“…Therefore, several drugs such as methotrexate, enalapril, fexofenadine, valsartan, olmesartan etc., that depend on efflux role of MRP2 for efficient biliary clearance should be expected to show altered pharmacokinetics in NASH patients (66). A recent example of decreased biliary efflux of both SN-38, active metabolite of irinotecan, and SN-38 glucuronide suggested the need of dose consideration in cancer patients when they are on irinotecan based chemotherapies (51).…”

“…As NASH can increase the risk of chronic kidney disease, the propensity of drug-drug interaction and dosage adjustment needs to be factored in the therapeutic management (72). Recent data suggesting the likelihood of lower expression of Cyp3A/CYP3A4 in the livers of NASH preclinical disease models and human NASH/NAFLD patients may be pertinent from therapy perspective of other concomitant drugs that are metabolized by CYP3A4 in humans (51). Finally, since NAFLD has been considered to present diagnosis of total metabolic syndrome from the liver manifestation; the co-existence of obesity, lipid disorders, blood pressure, and diabetes mellitus may further complicate the drug disposition of the chosen drug and present opportunities for victim and/or perpetrator kind of drug interactions (73).…”

“…Furthermore, the biliary excretion of pemetrexed was reduced by 60% in NASH rats as compared to normal animals. This study unravelled Mrp2 as the exclusive biliary elimination mechanism for pemetrexed making it a suitable in vivo probe substrate for Mrp2 function, and thereby, effectively accounting for the loss of function in NASH (50 (51). The impact of NASH on ADME properties based on preclinical and clinical reports are summarized in Table 2.…”