Multiple Compound-Related Adverse Properties Contribute to Liver Injury Caused by Endothelin Receptor Antagonists

Kenna, J. Gerry; Stahl, Simone; Eakins, Julie; Foster, Alison J.; Andersson, Linda C.; Bergare, Jonas; Billger, Martin; Elebring, Marie; Elmore, Charles S.; Thompson, Richard A.

doi:10.1124/jpet.114.220491

Cited by 42 publications

(42 citation statements)

References 32 publications

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“…Addition of extracellular bile acids in the cell-culture media caused increased cytotoxicity of liver spheroid cultures relative to normal media treated spheroid cultures treated with bosentan over 14 day (Hendriks et al 2016). In our studies, ambrisentan was not cytotoxic to hLiMT and has a reported 10- and 30-fold lower potency to inhibit BSEP transporter function than bosentan and sitax(s)entan, respectively (Kenna et al 2015). Taken together, the findings in this report in addition to the recent published report by Hendriks et al (2016) support that hLiMT may be a valuable in vitro tool to evaluate the functional and phenotypic (e.g., cytotoxicity) effects of bile-acid transport inhibition in an intact hepatocellular model.…”

Section: Discussionmentioning

confidence: 63%

“…Both drugs have strong association with DILI, where bosentan has been given a cautionary “black box” warning for DILI by the FDA and sitax(s)entan was voluntarily removed from the market due to hepatotoxicity concerns. Extensive studies, in particular on bosentan, support potential mechanisms of BSEP transport inhibition, and mitochondrial toxicity that lead to intrahepatic cholestasis and hepatocellular injury (Fattinger et al 2001; Kenna et al 2015). It remains unclear if the treatment time, enhanced liver phenotype, or presence of bile-canicular membranes were responsible for the increased sensitivity of hLiMT to these compounds relative to PHH in our studies.…”

Section: Discussionmentioning

confidence: 99%

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Utility of spherical human liver microtissues for prediction of clinical drug-induced liver injury

Proctor¹,

Foster

Vogt³

et al. 2017

Arch Toxicol

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234

244

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Drug-induced liver injury (DILI) continues to be a major source of clinical attrition, precautionary warnings, and post-market withdrawal of drugs. Accordingly, there is a need for more predictive tools to assess hepatotoxicity risk in drug discovery. Three-dimensional (3D) spheroid hepatic cultures have emerged as promising tools to assess mechanisms of hepatotoxicity, as they demonstrate enhanced liver phenotype, metabolic activity, and stability in culture not attainable with conventional two-dimensional hepatic models. Increased sensitivity of these models to drug-induced cytotoxicity has been demonstrated with relatively small panels of hepatotoxicants. However, a comprehensive evaluation of these models is lacking. Here, the predictive value of 3D human liver microtissues (hLiMT) to identify known hepatotoxicants using a panel of 110 drugs with and without clinical DILI has been assessed in comparison to plated two-dimensional primary human hepatocytes (PHH). Compounds were treated long-term (14 days) in hLiMT and acutely (2 days) in PHH to assess drug-induced cytotoxicity over an 8-point concentration range to generate IC50 values. Regardless of comparing IC50 values or exposure-corrected margin of safety values, hLiMT demonstrated increased sensitivity in identifying known hepatotoxicants than PHH, while specificity was consistent across both assays. In addition, hLiMT out performed PHH in correctly classifying hepatotoxicants from different pharmacological classes of molecules. The hLiMT demonstrated sufficient capability to warrant exploratory liver injury biomarker investigation (miR-122, HMGB1, α-GST) in the cell-culture media. Taken together, this study represents the most comprehensive evaluation of 3D spheroid hepatic cultures up to now and supports their utility for hepatotoxicity risk assessment in drug discovery.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-017-2002-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Utility of spherical human liver microtissues for prediction of clinical drug-induced liver injury

Proctor¹,

Foster

Vogt³

et al. 2017

Arch Toxicol

Self Cite

234

244

View full text Add to dashboard Cite

show abstract

“…[58][59][60] This knowledge has triggered the ''creation'' of a risk matrix, where effects on multiple mechanisms result in higher scores, which correlate with higher risk of causing human DILI. For more detail, please refer to Kenna et al 61 and Shah et al 62 Author Disclosure Statement Mohammed Taimi, Christopher Strock, Jonathan Gilbert, and Shuzhen Qin are employees of Cyprotex. The work presented here is a joint scientific collaboration.…”

Section: Less-dili Drugsmentioning

confidence: 98%

High-Content Imaging in Human and Rat Hepatocytes Using the Fluorescent Dyes CLF and CMFDA Is Not Specific Enough to Assess BSEP/Bsep and/or MRP2/Mrp2 Inhibition by Cholestatic Drugs

QiuLuping

FinleyJames

TaimiMohammed

et al. 2015

Applied In Vitro Toxicology

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Inhibition of hepatic efflux transporters (BSEP, MRP2) is one of the important mechanisms in drug-induced liver injury and in particular cholestasis. The inhibitory effect of compounds on these two hepatic transporters is commonly delineated using inverted membrane vesicles from Sf9 insect cells overexpressing the BSEP or MRP2 protein. However, due to lack of bioactivation and metabolism of the compound, and the lack of the expression and functionality of other sinusoidal efflux and uptake transporters in the cell-free assay system, it is difficult to fully understand the role of a given hepatic transporter in cholestasis. Therefore, our aim was to characterize and develop a competent cell-based bile canalicular imaging assay for measuring the overall inhibitory effects of compounds on biliary transport. Since species differences have been reported for some compounds, we developed the assay using both rat and human hepatocytes. Two fluorescent dyes, cholyl-lysyl-fluorescein (CLF) and carboxymethyl flourescein diacetate (CMFDA), have been reported in the literature to measure BSEP and MRP2 inhibition. We show in our study that neither CLF nor CMFDA is a specific substrate for either BSEP/Bsep or MRP2/ Mrp2 as demonstrated by generating K m values for each transporter. Most of the drugs tested inhibited CLF accumulation and exhibited less potency toward CMFDA accumulation in hepatocytes. We found the highest concordance between IC 50 values for inhibition of CLF accumulation in human hepatoyctes and IC 50 values generated in the human BSEP vesicle assay. This suggests that the human vesicle-based assays could suffice as a primary screen to avoid future potential human liver injury.

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“…123–125 Inhibition of bile acid transporters has been proposed as an underlying mechanism of sitaxsentan- and bosentan-mediated DILI. 103,126,127 On the other hand, recently approved ERAs, ambrisentan and macitentan, are associated with a lower risk of liver injury. 128–130 Studies using human SCH demonstrated that individual ERAs have differential effects on the hepatobiliary disposition of bile acids.…”

Section: Use Of Sandwich–cultured Hepatocytes To Study Drug–induced Lmentioning

confidence: 99%

Sandwich-Cultured Hepatocytes as a Tool to Study Drug Disposition and Drug-Induced Liver Injury

Yang

Guo

Woodhead

et al. 2016

Journal of Pharmaceutical Sciences

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Sandwich-cultured hepatocytes (SCH) are metabolically competent and have proper localization of basolateral and canalicular transporters with functional bile networks. Therefore, this cellular model is a unique tool that can be used to estimate biliary excretion of compounds. SCH have been used widely to assess hepatobiliary disposition of endogenous and exogenous compounds and metabolites. Mechanistic modeling based on SCH data enables estimation of metabolic and transporter-mediated clearances, which can be employed to construct physiologically-based pharmacokinetic models for prediction of drug disposition and drug-drug interactions in humans. In addition to pharmacokinetic studies, SCH also have been employed to study cytotoxicity and perturbation of biological processes by drugs and hepatically-generated metabolites. Human SCH can provide mechanistic insights underlying clinical drug-induced liver injury (DILI). In addition, data generated in SCH can be integrated into systems pharmacology models to predict potential DILI in humans. In this review, applications of SCH in studying hepatobiliary drug disposition and bile acid-mediated DILI are discussed. An example is presented to show how data generated in the SCH model was used to establish a quantitative relationship between intracellular bile acids and cytotoxicity, and how this information was incorporated into a systems pharmacology model for DILI prediction.

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Multiple Compound-Related Adverse Properties Contribute to Liver Injury Caused by Endothelin Receptor Antagonists

Cited by 42 publications

References 32 publications

Utility of spherical human liver microtissues for prediction of clinical drug-induced liver injury

Utility of spherical human liver microtissues for prediction of clinical drug-induced liver injury

High-Content Imaging in Human and Rat Hepatocytes Using the Fluorescent Dyes CLF and CMFDA Is Not Specific Enough to Assess BSEP/Bsep and/or MRP2/Mrp2 Inhibition by Cholestatic Drugs

Sandwich-Cultured Hepatocytes as a Tool to Study Drug Disposition and Drug-Induced Liver Injury

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