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
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.
Dr. Gerry Kenna is a safety science consultant based in Macclesfield, UK. Dr. Kenna provides expert advice to clients within the healthcare sector on generation and interpretation of preclinical and clinical safety data and is committed to the development and implementation of improved and mechanistically based drug safety screening and risk assessment strategies. He is a Network Partner in The Research Network (TRN; http://www.theresearchnetwork.co.uk ). This is an integrated team of which provides Pharmaceutical R&D scientific consultancy, project management, medicinal chemistry patent writing/strategy and due diligence services. Dr. Kenna has acquired extensive expertise in preclinical and clinical safety sciences (especially in assessment and management of drug induced liver injury) in industry and in academia and is involved actively in numerous programs of research on mechanisms which underlie human adverse drug reactions.
He held leadership roles as a molecular toxicologist and preclinical Hepatic Target Organ Strategy Leader in AstraZeneca. Prior to this, he supported safety assessment and registration of agrochemicals in the Zeneca/Syngenta Central Toxicology Laboratory UK. In 2011, Dr Kenna secured ~32 million Euro funding from the European Commission and EFPIA, via the Innovative Medicines Initiative, for a multi-disciplinary program of work on Mechanism based Improved Prediction of human Drug Induced Liver Injury (MIP-DILI) which involves numerous leading academic and industrial research groups. Before joining industry, Dr. Kenna was a Senior Lecturer in Pharmacology at St. Mary’s Hospital Medical School, London UK, where he founded and led a research group that investigated the role played by metabolic bioactivation and adaptive immune responses in human adverse drug reactions. This was preceded by independent research positions at the Laboratory of Chemical Pharmacology, National Institutes of Health USA; and the Liver Unit, King’s College Hospital, London UK. 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 >90 scientific publications, is a Fellow of the British Toxicology Society and is a Committee member of the International Society for the Study of Xenobiotics.
Bile acid transporters, bile flow and liver injury
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BSEP inhibition by drugs and DILI risk
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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.