Mechanistic Modeling Reveals the Critical Knowledge Gaps in Bile Acid–Mediated DILI

Woodhead, Jeffrey L.; Yang, Kunlun; Brouwer, Kim L. R.; Siler, Scott Q.; Stahl, Simone; Ambroso, Jeffrey L.; Baker, David H.; Watkins, Paul B.; Howell, Brett A.

doi:10.1038/psp.2014.21

Cited by 38 publications

(66 citation statements)

References 36 publications

(39 reference statements)

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“…A great amelioration is the incorporation of bile acid dynamics in the DILIsym [92], thus, the model includes not only the metabolic pathways, mitochondrial toxicity, key transporters, etc., but also the synthesis, uptake, recirculation, efflux, and hepatotoxicity of bile acids. This complex approach may help to reduce discrepancies originated from species differences as well as from in vitro and in vivo experimental data, thereby allowing improved prediction of BSEP-related DILI [92].…”

Section: In Silico Models For Predictions Of Cholestatic Effects Of Dmentioning

confidence: 99%

Recent advances in the exploration of the bile salt export pump (BSEP/ABCB11) function

Telbisz

Homolya

2015

Expert Opinion on Therapeutic Targets

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IntroductionThe bile salt export pump (BSEP/ABCB11), residing in the apical membrane of hepatocyte, mediates the secretion of bile salts into the bile. A range of human diseases is associated with the malfunction of BSEP, including fatal hereditary liver disorders and mild cholestatic conditions. Manifestation of these diseases primarily depends on the mutation type; however, other factors such as hormonal changes and drug interactions can also trigger or influence the related diseases. Areas coveredHere, we summarize the recent knowledge on BSEP by covering its transport properties, cellular localization, regulation, and major mutations/polymorphisms, as well as the hereditary and acquired diseases associated with BSEP dysfunction. We discuss the different model expression systems employed to understand the function of the BSEP variants, their drug interactions, and the contemporary therapeutic interventions. Expert opinionThe limitations of the available model expression systems for BSEP result in controversial conclusions, and obstruct our deeper insight into BSEP deficiencies and BSEPrelated drug interactions. The knowledge originating from different methodologies, such as clinical studies, molecular genetics, as well as in vitro and in silico modeling, should be integrated and harmonized. Increasing availability of robust molecular biological tools and our better understanding of the mechanism of BSEP deficiencies should make the personalized, mutation-based therapeutic interventions more attainable.

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Section: In Silico Models For Predictions Of Cholestatic Effects Of Dmentioning

confidence: 99%

Recent advances in the exploration of the bile salt export pump (BSEP/ABCB11) function

Telbisz

Homolya

2015

Expert Opinion on Therapeutic Targets

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“…Most importantly, the canalicular efflux transporter bile salt export pump (BSEP) seems to be the key player in the development of cholestatic DILI. This has been summarized by Vinken et al in an Adverse Outcome Pathway (AOP), and further confirmed by Woodhead et al by sensitivity analysis of a mechanistic model of cholestatic DILI (Vinken et al, 2013;Woodhead et al, 2014).…”

Section: Introductionmentioning

confidence: 84%

“…Kinetic parameters for the interaction of human transporters (NTCP, BSEP and OATPs) and bile acids are either not published with appropriate scaling factors or at best are available only for taurocholate, which is a minor BA in humans. In addition, Woodhead et al showed that BSEP abundance is the most important unknown kinetic parameter, that has a great influence on the outcome of the BA concentration in the liver in the presence of a BSEP inhibitor (Woodhead et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…An in silico model was recently described using DILIsym (Woodhead et al, 2014), in which BA handling in rat and human was modelled in the presence of a cholestatic drug (glibenclamide for rats and a theoretical cholestatic agent for humans). However, in this human model, many of the mechanistic parameters on hepatocellular bile acid handling were not experimentally determined, but were optimized by reverse-modeling, taking the clinical BA profile in humans as a starting point.…”

Section: Introductionmentioning

confidence: 99%

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Development of a mechanistic biokinetic model for hepatic bile acid handling to predict possible cholestatic effects of drugs

Notenboom

Weigand

Proost

et al. 2018

European Journal of Pharmaceutical Sciences

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A B S T R A C TDrug-induced liver injury (DILI) is a common reason for drug withdrawal from the market. An important cause of DILI is drug-induced cholestasis. One of the major players involved in drug-induced cholestasis is the bile salt efflux pump (BSEP; ABCB11). Inhibition of BSEP by drugs potentially leads to cholestasis due to increased (toxic) intrahepatic concentrations of bile acids with subsequent cell injury. In order to investigate the possibilities for in silico prediction of cholestatic effects of drugs, we developed a mechanistic biokinetic model for human liver bile acid handling populated with human in vitro data. For this purpose we considered nine groups of bile acids in the human bile acid pool, i.e. chenodeoxycholic acid, deoxycholic acid, the remaining unconjugated bile acids and the glycine and taurine conjugates of each of the three groups. Michaelis-Menten kinetics of the human uptake transporter Na + -taurocholate cotransporting polypeptide (NTCP; SLC10A1) and BSEP were measured using NTCP-transduced HEK293 cells and membrane vesicles from BSEP-overexpressing HEK293 cells. For in vitro-in vivo scaling, transporter abundance was determined by LC-MS/MS in these HEK293 cells and vesicles as well as in human liver tissue. Other relevant human kinetic parameters were collected from literature, such as portal bile acid levels and composition, bile acid synthesis and amidation rate. Additional empirical scaling was applied by increasing the excretion rate with a factor 2.4 to reach near physiological steady-state intracellular bile acid concentrations (80 μM) after exposure to portal vein bile acid levels. Simulations showed that intracellular bile acid concentrations increase 1.7 fold in the presence of the BSEP inhibitors and cholestatic drugs cyclosporin A or glibenclamide, at intrahepatic concentrations of 6.6 and 20 μM, respectively. This simplified model provides a tool for a first indication whether drugs at therapeutic concentrations might cause cholestasis by inhibiting BSEP.

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“…The full set of equations for DILIsym version 3A (and indeed for all versions of DILIsym past and present) is fully available to the members of the Initiative. Importantly, key equations from DILIsym have been published in the literature, including equations related to oxidative stress,5 bile acid homeostasis and transporter disruption,7, 9 mitochondrial dysfunction,10 and the dynamics of the innate immune system 11. These previous publications also provide significant insight into the scientific theory and knowledge behind the development of DILIsym.…”

Section: Methodsmentioning

confidence: 99%

Prediction of Safety Margin and Optimization of Dosing Protocol for a Novel Antibiotic using Quantitative Systems Pharmacology Modeling

Woodhead

Paech

Maurer

et al. 2018

Clinical Translational Sci

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Elevations of liver enzymes have been observed in clinical trials with BAL30072, a novel antibiotic. In vitro assays have identified potential mechanisms for the observed hepatotoxicity, including electron transport chain (ETC) inhibition and reactive oxygen species (ROS) generation. DILIsym, a quantitative systems pharmacology (QSP) model of drug‐induced liver injury, has been used to predict the likelihood that each mechanism explains the observed toxicity. DILIsym was also used to predict the safety margin for a novel BAL30072 dosing scheme; it was predicted to be low. DILIsym was then used to recommend potential modifications to this dosing scheme; weight‐adjusted dosing and a requirement to assay plasma alanine aminotransferase (ALT) daily and stop dosing as soon as ALT increases were observed improved the predicted safety margin of BAL30072 and decreased the predicted likelihood of severe injury. This research demonstrates a potential application for QSP modeling in improving the safety profile of candidate drugs.

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Mechanistic Modeling Reveals the Critical Knowledge Gaps in Bile Acid–Mediated DILI

Cited by 38 publications

References 36 publications

Recent advances in the exploration of the bile salt export pump (BSEP/ABCB11) function

Recent advances in the exploration of the bile salt export pump (BSEP/ABCB11) function

Development of a mechanistic biokinetic model for hepatic bile acid handling to predict possible cholestatic effects of drugs

Prediction of Safety Margin and Optimization of Dosing Protocol for a Novel Antibiotic using Quantitative Systems Pharmacology Modeling

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