Current insights in the complexities underlying drug-induced cholestasis

Abstract

Drug-induced cholestasis (DIC) poses a major challenge to the pharmaceutical industry and regulatory agencies. It causes both drug attrition and post-approval withdrawal of drugs. DIC represents itself as an impaired secretion and flow of bile, leading to the pathological hepatic and/or systemic accumulation of bile acids (BAs) and their conjugate bile salts. Due to the high number of mechanisms underlying DIC, predicting a compound's cholestatic potential during early stages of drug development remains elusive. A profound understanding of the different molecular mechanisms of DIC is, therefore, of utmost importance. Although many knowledge gaps and caveats still exist, it is generally accepted that alterations of certain hepatobiliary membrane transporters and changes in hepatocellular morphology may cause DIC. Consequently, liver models, which represent most of these mechanisms, are valuable tools to predict human DIC. Some of these models, such as membrane-based in vitro models, are exceptionally well-suited to investigate specific mechanisms (i.e., transporter inhibition) of DIC, while others, such as liver slices, encompass all relevant biological processes and therefore offer a better representation of the in vivo situation. In the current review, we highlight the principal molecular mechanisms associated with DIC and offer an overview and critical appraisal of the different liver models that are currently being used to predict the cholestatic potential of drugs.

Drug-induced cholestasis assay in primary hepatocytes

“…Preclinical assays for DIC detection often rely on evaluation of the test compound towards individual cellular targets such as their inhibitory potential towards the bile salt export pump (BSEP) by using BSEP membrane vesicles [2 , 3] . However, the underlying mechanisms of DIC development are more complex involving multiple other transporters and nuclear receptors [4] . A more comprehensive in vitro model such as sandwich-cultured human hepatocytes (SCHH) are more suited due to the presence of metabolizing enzymes and transporters relevant to bile salt disposition [5] .…”

Drug-induced liver injury after switching from tamoxifen to anastrozole in a patient with a history of breast cancer being treated for hypertension and diabetes

“…We also studied selected systematic reviews and guidelines describing types of DILI 13,14,32 as well as articles explaining potential drug-drug interactions associated with membrane transporters. 15,16,[33][34][35][36][37] Anastrozole is a substrate for the CYP3A4 enzyme, but it is not a substrate for the P-glycoprotein. Amlodipine and gliquidone were identified as inhibitors of both the CYP3A4 enzyme and P-glycoprotein, which could result in an increase in systemic exposure to drugs that are substrates for CYP3A4 and P-glycoprotein.…”

“…Wishart et al, 4 Konig et al, 33 Deferm et al, 37 Jansen, 54 Fernández-Murga et al 55 Hepatocyte membrane 4 Yang et al 16 Giacomini and Sugiyama, 40 Hu et al, 41 Corsini and Keppler, 35 Deferm et al, 37 Kock et al, 47 Ivanyuk et al 53 4 Weiss et al, 36 Hu et al, 41 Ivanyuk et al 53 The other drugs were taken before admission to the hospital and also in the hospital. BCRP/ABCG2, breast cancer resistant protein/ATP-binding cassette subfamily G2; BSEP/ABCB-11, bile salt export pump/ATP-binding cassette protein subfamily B-11; MDR-1, multidrug resistance protein-1 or P-glycoprotein is an expression for ABCB1; MRP-2/ABCC2, multidrug resistance-associated protein-2/ATP-binding cassette protein subfamily C 2; MRP-3/ABCC3, multidrug resistance-associated protein-3/ATP-binding cassette protein subfamily C-3; MRP-4/ABCC4, multidrug resistance-associated protein-4/ATP-binding cassette protein subfamily C-4; NTCP, sodium taurocholate co-transporter polypeptide that is, solute carrier family 10 transporter A1; OATP1B1, organic anion transport protein 1B1 that is, SLCO 1B1, solute carrier organic anion transporter family member 1B1; OCT1, organic cation transporter, that is, SLC22A1, solute carrier family 22 transporter A1; OCTN2, organic cation/carnitine transporter.…”

A Two-Tiered In Vitro Approach to De-Risk Drug Candidates for Potential Bile Salt Export Pump Inhibition Liabilities in Drug Discovery

“…Importantly, our analysis in MPCCs does not consider the type of DILI associated with a compound, but rather focuses on potential to inhibit biliary efflux. Since inhibition of biliary efflux is only one potential mechanism causing/correlating with cholestatic liver injury (Balistreri et al, 2005, Burbank et al, 2016, Deferm et al, 2019, compounds known to be cholestatic in humans such as troglitazone, nefazodone, and bosentan may or may not be flagged using a 10-fold cutoff between the TCA BEI IC 50 and fu*I in,max indicating altered transporter-mediated efflux.…”