Role of inhibition of the bile salt export pump (BSEP) in drug induced liver injury

Date: November 26 2013
Presenter(s): Gerry Kenna, Safety Science Consultant, Macclesfield UK

Role of inhibition of the bile salt export pump (BSEP) in drug induced liver injury
Webinar presented on November 26th, 2013 by Gerry Kenna, Safety Science Consultant, Macclesfield UK

Summary of the presentation

Bile acids are synthesized within hepatocytes and excreted into bile by ATP-dependent active transport proteins located on the apical plasma membrane domain, most notably the Bile Salt Export Pump (BSEP, ABCB11). Impaired BSEP activity results in accumulation of bile acids within hepatocytes which can cause cholestatic liver injury. In humans, defective BSEP activity may arise as a consequence of genetically inherited BSEP gene mutations. The most severe functional consequence is Progressive Familial Intrahepatic Cholestasis type 2, which is characterised by early onset cholestasis soon after birth and subsequent progressive degenerative liver injury that is fatal unless treated by liver transplantation. Many drugs which cause infrequent but clinically severe liver injury (iDILI) in humans have been found to inhibit BSEP activity in vitro using a variety of different experimental model systems, and in vivo in experimental animals. For a wide variety of drugs a correlation has also been observed between propensity to cause DILI in humans, potency of in vitro BSEP inhibition and their therapeutic plasma drug concentrations.

These findings suggest that BSEP inhibition could be an important mechanism which helps explain how some drugs initiate DILI. Recently, BSEP has been highlighted by the International Transporter Consortium as one of the emerging transporters which need to be considered when evaluating drug safety. Several groups of researchers have proposed that pro-active in vitro screening for BSEP during drug discovery may aid in early flagging and deselection of compounds which have high propensity to cause iDILI. The practical utility of this approach is being evaluated within several pharmaceutical companies. BSEP inhibition is one of several adverse properties which appear to play important roles in initiation of iDILI, therefore screening for in vitro BSEP inhibition is likely to be of greatest value if undertaken alongside screening for other relevant adverse effects (e.g. mitochondrial injury, cell cytotoxicity, metabolic bioactivation).

Currently, our understanding of the contribution of physicochemical and molecular properties to the BSEP inhibition potential of new chemical entities is in its infancy. Nonetheless, in the future it can be envisaged that robust in silico QSAR models will aid in the design of molecules that are unlikely to inhibit BSEP and will thereby inform and guide in vitro testing strategies. To enhance assessment and management of the safety risk posed by BSEP inhibition, such in silico and in vitro tools will need to be complemented by approaches thath provide insight into functional adverse consequences which arise in vivo. A promising option is provided by noninvasive whole body imaging of hepatic uptake and biliary excretion of probe substrates, e.g. gadoxetate.

Literature References provided by Dr. Gerry Kenna

Bile acid transporters, bile flow and liver injury
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3. Soroka CJ, Boyer JL. Biosynthesis and trafficking of the bile salt export pump, BSEP: Therapeutic implications of BSEP mutations. Mol Aspects Med. 2013 May 15. doi:pii: S0098-2997(13)00034-4. 10.1016/j.mam.2013.05.001. [Epub ahead of print] PMID: 23685087

BSEP inhibition by drugs and DILI risk
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1. Sakurai A, Kurata A, Onishi Y, Hirano H, Ishikawa T. Prediction of drug-induced intrahepatic cholestasis: in vitro screening and QSAR analysis of drugs inhibiting the human bile salt export pump. Expert Opin Drug Saf. 2007 Jan;6(1):71-86.
2. Warner DJ, Chen H, Cantin LD, Kenna JG, Stahl S, Walker CL, Noeske T. Mitigating the inhibition of human bile salt export pump by drugs: opportunities provided by physicochemical property modulation, in silico modeling, and structural modification. Drug Metab Dispos. 2012 Dec;40(12):2332-41.

In vivo imaging
1. Ulloa JL, Stahl S, Yates J, Woodhouse N, Kenna JG, Jones HB, Waterton JC, Hockings PD. Assessment of gadoxetate DCE-MRI as a biomarker of hepatobiliary transporter inhibition. NMR Biomed. 2013 Oct;26(10):1258-70.

Integrated assessment of BSEP inhibition and other drug related DILI risk factors
1. Thompson RA, Isin EM, Li Y, Weaver R, Weidolf L, Wilson I, Claesson A, Page K, Dolgos H, Kenna JG. Risk assessment and mitigation strategies for reactive metabolites in drug discovery and development. Chem Biol Interact. 2011 Jun 30;192(1-2):65-71.
2. Thompson RA, Isin EM, Li Y, Weidolf L, Page K, Wilson I, Swallow S, Middleton B, Stahl S, Foster AJ, Dolgos H, Weaver R, Kenna JG. In vitro approach to assess the potential for risk of idiosyncratic adverse reactions caused by candidate drugs. Chem Res Toxicol. 2012 Aug 20;25(8):1616-32.

International Transporter Consortium
1. Zamek-Gliszczynski MJ, Hoffmaster KA, Tweedie DJ, Giacomini KM, Hillgren KM. Highlights from the International Transporter Consortium second workshop. Clin Pharmacol Ther. 2012 Nov;92(5):553-6.
2. Hillgren KM, Keppler D, Zur AA, Giacomini KM, Stieger B, Cass CE, Zhang L; International Transporter Consortium. Emerging transporters of clinical importance: an update from the International Transporter Consortium. Clin Pharmacol Ther. 2013 Jul;94(1):52-63.

About the presenter:

KENNA Gerry, PhD

Drug Safety Consultant Macclesfield, Cheshire, United Kingdom


Dr. Gerry Kenna is a Drug Safety Consultant based in Cheshire, UK. He has extensive experience of safety assessment of pharmaceuticals and other chemicals and of toxicity testing and of mechanisms that underlie human adverse drug reactions, most notably liver toxicity. This was acquired while working as Scientific Director of FRAME (the Fund for the Replacement of Animals in Medical Experiments;; in industry for AstraZeneca, Syngenta and Zeneca; and in academia at Imperial College School of Medicine, London UK; National Institutes of Health, MD USA; King’s College Hospital Medical School, London UK and the National Institute for Medical Research, London UK. Dr. Kenna continues to be actively involved in research on the mechanisms which underlie human adverse drug reactions and on the development and implementation of novel predictive safety screening strategies that take account of hepatobiliary transporter inhibition, metabolic bioactivation and immune responsiveness, plus PBPK-based in vitro/in vivo exposure scaling. He is also committed to implementation of improved human safety testing strategies that reduce, refine and replace a need for procedures on animals. Dr Kenna received a BSc in Biochemistry from the University of Leeds UK and a PhD in Biochemistry from the University of London UK. He has authored or co-authored >100 scientific publications and is a member of the International Society for the Study of Xenobiotics, and a Fellow of the British Toxicology Society.