A Change in Bile Flow: Looking Beyond Transporter Inhibition in the Development of Drug-induced Cholestasis

Abstract

Background: Drug-induced Liver Injury (DILI) has received increasing attention over the past decades, as it represents the leading cause of drug failure and attrition. One of the most prevalent and severe forms of DILI involves the toxic accumulation of bile acids in the liver, known as Drug-induced Cholestasis (DIC). Traditionally, DIC is studied by exploring the inhibition of hepatic transporters such as Bile Salt Export Pump (BSEP) and multidrug resistance-associated proteins, predominantly through vesicular transport assays. Although this approach has identified numerous drugs that alter bile flow, many DIC drugs do not demonstrate prototypical transporter inhibition, but rather are associated with alternative mechanisms. Methods: We undertook a focused literature search on DIC and biliary transporters and analyzed peer-reviewed publications over the past two decades or so. Results: We have summarized the current perception regarding DIC, biliary transporters, and transcriptional regulation of bile acid homeostasis. A growing body of literature aimed to identify alternative mechanisms in the development of DIC has been evaluated. This review also highlights current in vitro approaches used for prediction of DIC. Conclusion: Efforts have continued to focus on BSEP, as it is the primary route for hepatic biliary clearance. In addition to inhibition, drug-induced BSEP repression or the combination of these two has emerged as important alternative mechanisms leading to DIC. Furthermore, there has been an evolution in the approaches to studying DIC including 3D cell cultures and computational modeling.

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“…Because the inhibitory potency of BSEP alone is usually not sufficient to determine DILI risk during pharmacotherapy, 30 we made a table of known drug and drug metabolite effects on membrane transporters, particularly as they related to hepatobiliary or renal activity (Table 3). 48–54…”

“…Because the inhibitory potency of BSEP alone is usually not sufficient to determine DILI risk during pharmacotherapy, 30 we made a table of known drug and drug metabolite effects on membrane transporters, particularly as they related to hepatobiliary or renal activity (Table 3). [48][49][50][51][52][53][54] Besides the potential contribution of impaired bile acid homeostasis, mechanisms such as the immune-mediated hypersensitivity reaction, dose, and lipophilicity of the drug itself, as well as combinations of these factors together with individual risk factors, seem to be important in the onset of acute DILI. 56 In addition, drug-drug interactions can alter a drug's toxicity profile, which could potentially lead to hepatotoxicity.…”

Robust and Comprehensive Targeted Metabolomics Method for Quantification of 50 Different Primary, Secondary, and Sulfated Bile Acids in Multiple Biological Species (Human, Monkey, Rabbit, Dog, and Rat) and Matrices (Plasma and Urine) Using Liquid Chromatography High Resolution Mass Spectrometry (LC-HRMS) Analysis

“…BAs hold promise as biomarkers which can be used to better understand DILI in both nonclinical and clinical settings as BA homeostasis is intricately involved in liver function. 14,21 A search for early detection of "BAs signature" changes caused by disruption of BA homeostasis can be a valuable tool for DILI assessment preclinically and clinically during drug development. 21 Such BA signatures changes can also be used to assess general liver and gut function in the context of hepatic and intestinal disorders.…”

“…Disruption of bile acid homeostasis is known to happen in several hepatic, intestinal, and gall bladder related diseases and drug induced liver toxicity (DILI), which is an important area of research within pharmaceutical and biopharmaceutical drug development. − Drug dependent DILI can lead to acute hepatitis or cholestatic injury causing cholestasis or some mixed response . DILI might also be drug independent by action of idiosyncratic or immune mediated mechanisms .…”

Tanshinone ⅡA may alleviate rifampin-induced cholestasis by regulating the expression and function of NTCP

“…2 When bile flow is impeded in enterohepatic circulation, toxic bile acids accumulate in the liver or penetrate into the blood, leading to liver injury. 3 Drugs can affect bile flow and bile acid reabsorption, 4 causing drug-induced liver injury (DILI).…”