The hepatocyte export carrier inhibition assay improves the separation of hepatotoxic from non-hepatotoxic compounds

Brecklinghaus, Tim; Albrecht, Wiebke; Kappenberg, Franziska; Duda, Julia; Vartak, Nachiket; Edlund, Karolina; Marchan, Rosemarie; Ghallab, Ahmed; Cadenas, Cristina; Günther, Georgia; Leist, Marcel; Zhang, Mian; Gardner, Iain; Reinders, Jörg; Rüssel, Frans G. M.; Foster, Alison J.; Williams, Dominic P.; Damle-Vartak, Amruta; Grandits, Melanie; Ecker, Gerhard; Kittana, Naim; Rahnenführer, Jörg; Hengstler, Jan G.

doi:10.1016/j.cbi.2021.109728

Cited by 20 publications

(10 citation statements)

References 37 publications

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“…There are several compensatory mechanisms in the human liver to counteract hepatic BA accumulation involving the upregulation of other efflux transporters, e.g., OSTα/β and MRP3/4 (Gijbels et al 2020;Jackson et al 2016). Even though BSEP inhibition does not necessarily lead to cholestasis, it has been shown that integrating an export assay that measures the inhibition of BA export improves hepatotoxicity predictions compared to a cytotoxicity test in primary hepatocytes alone (Brecklinghaus et al 2022).…”

Section: Introductionmentioning

confidence: 99%

Population pharmacokinetic model to generate mechanistic insights in bile acid homeostasis and drug-induced cholestasis

2022

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Bile acids (BA) fulfill a wide range of physiological functions, but are also involved in pathologies, such as cholestasis. Cholestasis is characterized by an intrahepatic accumulation of BAs and subsequent spillage to the systemic circulation. The aim of the present study was to develop physiologically based kinetic (PBK) models that would provide a tool to predict dose-dependent BA accumulation in humans upon treatment with a Bile Salt Export Pump (BSEP) inhibitor. We developed a PBK model describing the BA homeostasis using glycochenodeoxycholic acid as an exemplary BA. Population wide distributions of BSEP abundances were incorporated in the PBK model using Markov Chain Monte Carlo simulations, and alternatively the total amount of BAs was scaled empirically to describe interindividual differences in plasma BA levels. Next, the effects of the BSEP inhibitor bosentan on the BA levels were simulated. The PBK model developed adequately predicted the in vivo BA dynamics. Both the Markov Chain Monte Carlo simulations based on a distribution of BSEP abundances and empirical scaling of the total BA pool readily described the variations within and between data in human volunteers. Bosentan treatment disproportionally increased the maximum BA concentration in individuals with a large total BA pool or low BSEP abundance. Especially individuals having a large total BA pool size and a low BSEP abundance were predicted to be at risk for rapid saturation of BSEP and subsequent intrahepatic BA accumulation. This model provides a first estimate of personalized safe therapeutic external dose levels of compounds with BSEP-inhibitory properties.

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Section: Introductionmentioning

confidence: 99%

Population pharmacokinetic model to generate mechanistic insights in bile acid homeostasis and drug-induced cholestasis

2022

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“…While bile production in ICOs was shown to be low compared to HepaRGs and PHHs, ICOs were more sensitive in drug-induced phospholipidosis screening compared to HepG2 cells. A unique feature of HL-ICOs is their polarization and relative expression of hepatic transporters compared to PHHs, suggesting possibilities for HL-ICOs in toxicity screens involving transporters that are important in toxicity prediction [ 64 ]. Further characterization of the functionality of HL-ICOs, for example, using a comprehensive phase II enzyme activity assay [ 65 , 66 ], and their predictive potential to compound toxicity using a more extensive set of test compounds and readouts in a high-throughput fashion [ 67 , 68 ], will illustrate their potential in in vitro toxicity testing.…”

Section: Discussionmentioning

confidence: 99%

Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing

et al. 2023

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Emerging advances in the field of in vitro toxicity testing attempt to meet the need for reliable human-based safety assessment in drug development. Intrahepatic cholangiocyte organoids (ICOs) are described as a donor-derived in vitro model for disease modelling and regenerative medicine. Here, we explored the potential of hepatocyte-like ICOs (HL-ICOs) in in vitro toxicity testing by exploring the expression and activity of genes involved in drug metabolism, a key determinant in drug-induced toxicity, and the exposure of HL-ICOs to well-known hepatotoxicants. The current state of drug metabolism in HL-ICOs showed levels comparable to those of PHHs and HepaRGs for CYP3A4; however, other enzymes, such as CYP2B6 and CYP2D6, were expressed at lower levels. Additionally, EC50 values were determined in HL-ICOs for acetaminophen (24.0–26.8 mM), diclofenac (475.5–>500 µM), perhexiline (9.7–>31.5 µM), troglitazone (23.1–90.8 µM), and valproic acid (>10 mM). Exposure to the hepatotoxicants showed EC50s in HL-ICOs comparable to those in PHHs and HepaRGs; however, for acetaminophen exposure, HL-ICOs were less sensitive. Further elucidation of enzyme and transporter activity in drug metabolism in HL-ICOs and exposure to a more extensive compound set are needed to accurately define the potential of HL-ICOs in in vitro toxicity testing.

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“…In vitro inhibition of BSEP by certain drugs, such as cyclosporin A, bosentan or troglitazone, has been demonstrated to correlate with the risk of these drugs for cholestatic DILI [ 97 , 98 , 99 ]. More recently, it was shown that by a fluorescein export assay, which analyzes both the inhibition of BSEP and of multidrug-resistance-associated protein 2 (MRP2), it was possible to distinguish between hepatotoxic and non-hepatotoxic agents [ 100 ]. Based on these findings, industry and medical regulatory agencies, such as the EMA and the FDA, have proposed to implement BSEP inhibition testing into drug development schemes [ 101 , 102 , 103 ].…”

Section: Prediction Of Dili—where Do We Stand?mentioning

confidence: 99%

Challenges and Future of Drug-Induced Liver Injury Research—Laboratory Tests

Weber

Gerbes

2022

IJMS

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Drug-induced liver injury (DILI) is a rare but potentially severe adverse drug event, which is also a major cause of study cessation and market withdrawal during drug development. Since no acknowledged diagnostic tests are available, DILI diagnosis poses a major challenge both in clinical practice as well as in pharmacovigilance. Differentiation from other liver diseases and the identification of the causative agent in the case of polymedication are the main issues that clinicians and drug developers face in this regard. Thus, efforts have been made to establish diagnostic testing methods and biomarkers in order to safely diagnose DILI and ensure a distinguishment from alternative liver pathologies. This review provides an overview of the diagnostic methods used in differential diagnosis, especially with regards to autoimmune hepatitis (AIH) and drug-induced autoimmune hepatitis (DI-AIH), in vitro causality methods using individual blood samples, biomarkers for diagnosis and severity prediction, as well as experimental predictive models utilized in pre-clinical settings during drug development regimes.

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The hepatocyte export carrier inhibition assay improves the separation of hepatotoxic from non-hepatotoxic compounds

Cited by 20 publications

References 37 publications

Population pharmacokinetic model to generate mechanistic insights in bile acid homeostasis and drug-induced cholestasis

Population pharmacokinetic model to generate mechanistic insights in bile acid homeostasis and drug-induced cholestasis

Drug Metabolism of Hepatocyte-like Organoids and Their Applicability in In Vitro Toxicity Testing

Challenges and Future of Drug-Induced Liver Injury Research—Laboratory Tests

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