Current Concepts in Drug‐Induced Bile Salt Export Pump (BSEP) Interference

Kenna, J. Gerry

doi:10.1002/0471140856.tx2307s61

Cited by 19 publications

(7 citation statements)

References 64 publications

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“…Early detection of DILI (particularly, cholestasis) remains a challenge for pharmaceutical industries and regulatory agencies. According to the International Transporter Consortium and guidelines on the investigation of drug interactions from the European Medicines Agency (Zamek-Gliszczynski et al, 2012), inhibition of the bile salt export pump (BSEP), which plays a major role in BA canalicular transport (Jansen et al, 1999;Stieger, 2010), should be evaluated during drug development when evidence of cholestatic liver injury has been observed in nonclinical safety studies or in human clinical trials (Kenna, 2014). Indeed, many drugs reported to cause DILI have been identified as efflux transporter inhibitors (Morgan et al, 2010;Stieger, 2010;Dawson et al, 2012;Pedersen et al, 2013), but a significant number of false positives has been found (Pedersen et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Early Alterations of Bile Canaliculi Dynamics and the Rho Kinase/Myosin Light Chain Kinase Pathway Are Characteristics of Drug-Induced Intrahepatic Cholestasis

Burbank

Burban

Sharanek

et al. 2016

Drug Metabolism and Disposition

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Intrahepatic cholestasis represents 20%-40% of drug-induced injuries from which a large proportion remains unpredictable. We aimed to investigate mechanisms underlying drug-induced cholestasis and improve its early detection using human HepaRG cells and a set of 12 cholestatic drugs and six noncholestatic drugs. In this study, we analyzed bile canaliculi dynamics, Rho kinase (ROCK)/myosin light chain kinase (MLCK) pathway implication, efflux inhibition of taurocholate [a predominant bile salt export pump (BSEP) substrate], and expression of the major canalicular and basolateral bile acid transporters. We demonstrated that 12 cholestatic drugs classified on the basis of reported clinical findings caused disturbances of both bile canaliculi dynamics, characterized by either dilatation or constriction, and alteration of the ROCK/MLCK signaling pathway, whereas noncholestatic compounds, by contrast, had no effect. Cotreatment with ROCK inhibitor Y-27632 [4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride] and MLCK activator calmodulin reduced bile canaliculi constriction and dilatation, respectively, confirming the role of these pathways in drug-induced intrahepatic cholestasis. By contrast, inhibition of taurocholate efflux and/or human BSEP overexpressed in membrane vesicles was not observed with all cholestatic drugs; moreover, examples of noncholestatic compounds were reportedly found to inhibit BSEP. Transcripts levels of major bile acid transporters were determined after 24-hour treatment. BSEP, Na-taurocholate cotransporting polypeptide, and organic anion transporting polypeptide B were downregulated with most cholestatic and some noncholestatic drugs, whereas deregulation of multidrug resistance-associated proteins was more variable, probably mainly reflecting secondary effects. Together, our results show that cholestatic drugs consistently cause an early alteration of bile canaliculi dynamics associated with modulation of ROCK/MLCK and these changes are more specific than efflux inhibition measurements alone as predictive nonclinical markers of drug-induced cholestasis.

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Section: Introductionmentioning

confidence: 99%

Early Alterations of Bile Canaliculi Dynamics and the Rho Kinase/Myosin Light Chain Kinase Pathway Are Characteristics of Drug-Induced Intrahepatic Cholestasis

Burbank

Burban

Sharanek

et al. 2016

Drug Metabolism and Disposition

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“…Plasma bile acid monitoring in animals has been proposed to provide a useful indirect biomarker of in vivo BSEP function (also see section “Data Interpretation: In Vitro/In Vivo Extrapolation, Quantitative Simulations”). However, increased plasma bile acid concentrations may also arise due to extrahepatic biliary obstruction, or as a secondary consequence of hepatocellular liver damage .…”

Section: Data Interpretation: In Vitro/in Vivo Extrapolation Quantitmentioning

confidence: 99%

Can Bile Salt Export Pump Inhibition Testing in Drug Discovery and Development Reduce Liver Injury Risk? An International Transporter Consortium Perspective

Kenna

Taskar

Battista

et al. 2018

Clin Pharma and Therapeutics

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Bile salt export pump (BSEP) inhibition has emerged as an important mechanism that may contribute to the initiation of human drug‐induced liver injury (DILI). Proactive evaluation and understanding of BSEP inhibition is recommended in drug discovery and development to aid internal decision making on DILI risk. BSEP inhibition can be quantified using in vitro assays. When interpreting assay data, it is important to consider in vivo drug exposure. Currently, this can be undertaken most effectively by consideration of total plasma steady state drug concentrations (Css,plasma). However, because total drug concentrations are not predictive of pharmacological effect, the relationship between total exposure and BSEP inhibition is not causal. Various follow‐up studies can aid interpretation of in vitro BSEP inhibition data and may be undertaken on a case‐by‐case basis. BSEP inhibition is one of several mechanisms by which drugs may cause DILI, therefore, it should be considered alongside other mechanisms when evaluating possible DILI risk.

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“…6, 8, and 17). In addition, inhibition of the activity of the biliary efflux transporter BSEP plays a direct role in the mechanism by which numerous drugs can initiate DILI, while upregulation of the activity of other biliary efflux transporters plays an important hepatoprotective role in response to BSEP inhibition by drugs [11] (see also Chap. 15).…”

Section: Hepatobiliary Imaging Modalities and Tracersmentioning

confidence: 99%

“…A limitation of gadoxetate DCE-MRI is that, since gadoxetate is not transported by BSEP, it does not enable direct investigation of drug-induced inhibition of BSEP activity, which is considered to play an important role in DILI caused by many drugs [11]. Other probe substrates that are transported by BSEP, and ideally are BSEP-specific, are needed.…”

Section: Future Opportunities and Challengesmentioning

confidence: 99%

Noninvasive Preclinical and Clinical Imaging of Liver Transporter Function Relevant to Drug-Induced Liver Injury

Kenna

Waterton

Baudy

et al. 2018

Methods in Pharmacology and Toxicology

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Imaging technologies can evaluate many different biological processes in vitro (in cell culture models) and in vivo (in animals and humans), and many are used routinely in investigation of human liver diseases. Some of these methods can help understand liver toxicity caused by drugs in vivo in animals, and druginduced liver injury (DILI) which arises in susceptible humans. Imaging could aid assessment of the relevance to humans in vivo of toxicity caused by drugs in animals (animal/human translation), plus toxicities observed using in vitro model systems (in vitro/in vivo translation). Technologies and probe substrates for quantitative evaluation of hepatobiliary transporter activities are of particular importance. This is due to the key role played by sinusoidal transporter mediated hepatic uptake in DILI caused by many drugs, plus the strong evidence that inhibition of the hepatic bile salt export pump (BSEP) can initiate DILI. Imaging methods for investigation of these processes are reviewed in this chapter, together with their scientific rationale, and methods of quantitative data analysis. In addition to providing biomarkers for investigation of DILI, such approaches could aid the evaluation of clinically relevant drug-drug interactions mediated via hepatobiliary transporter perturbation.

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Current Concepts in Drug‐Induced Bile Salt Export Pump (BSEP) Interference

Cited by 19 publications

References 64 publications

Early Alterations of Bile Canaliculi Dynamics and the Rho Kinase/Myosin Light Chain Kinase Pathway Are Characteristics of Drug-Induced Intrahepatic Cholestasis

Early Alterations of Bile Canaliculi Dynamics and the Rho Kinase/Myosin Light Chain Kinase Pathway Are Characteristics of Drug-Induced Intrahepatic Cholestasis

Can Bile Salt Export Pump Inhibition Testing in Drug Discovery and Development Reduce Liver Injury Risk? An International Transporter Consortium Perspective

Noninvasive Preclinical and Clinical Imaging of Liver Transporter Function Relevant to Drug-Induced Liver Injury

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