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

J. Gerry Kenna1

1 Safety Science Consultant, Macclesfield, Cheshire
Publication Name:  Current Protocols in Toxicology
Unit Number:  Unit 23.7
DOI:  10.1002/0471140856.tx2307s61
Online Posting Date:  August, 2014
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Abstract

Numerous drugs have been shown to inhibit the activity of the Bile Salt Export Pump (BSEP in humans, Bsep in animals), and this is now considered to be one of several mechanisms by which idiosyncratic drug‐induced liver injury (DILI) may be initiated in susceptible patients. The potential importance of BSEP inhibition by drugs has been recognized by the European Medicines Agency and the International Transporter Consortium, who have recommended that it should be evaluated during drug development when evidence of cholestatic liver injury has been observed in nonclinical safety studies or in human clinical trials. In addition, some pharmaceutical companies have proposed evaluation and minimization of BSEP inhibition during drug discovery, when there is a chemical choice, to help reduce DILI risk. The methods that can be used to assess and quantify BSEP inhibition, and key gaps in our current understanding of the relationship between this process and DILI, are discussed. Curr. Protoc. Toxicol. 61.23.7.1:‐23.7.15. © 2014 by John Wiley & Sons, Inc.

Keywords: drug‐induced liver injury; cholestasis; bile salt; ABCB11; drug safety screening

     
 
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Table of Contents

  • Role of BSEP Inhibition in Human Cholestatic Liver Injury
  • BSEP Inhibition and Drug‐Induced Liver Injury (DILI)
  • Methods for Evaluation of BSEP Inhibition and their Pitfalls
  • Data and Knowledge Gaps
  • Literature Cited
  • Tables
     
 
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Literature Cited

Literature Cited
  Abboud, G. and Kaplowitz, N. 2007. Drug‐induced liver injury. Drug Safety 30:277‐294.
  Bhattacharya, S., Shoda, L.K., Zhang, Q., Woods, C.G., Howell, B.A., Siler, S.Q., Woodhead, J.L., Yang, Y., McMullen, P., Watkins, P.B., and Andersen, M.E. 2012. Modeling drug‐ and chemical‐induced hepatotoxicity with systems biology approaches. Front. Physiol. 3:462.
  Böhme, M., Müller, M., Leier, I., Jedlitschky, G., and Keppler, D. 1994. Cholestasis caused by inhibition of the adenosine triphosphate‐dependent bile salt transport in rat liver. Gastroenterol 107:255‐265.
  Chu, X., Korzekwa, K., Elsby, R., Fenner, K., Galetin, A., Lai, Y., Matsson, P., Moss, A., Nagar, S., Rosania, G.R., Bai, J.P., Polli, J.W., Sugiyama, Y., Brouwer, K.L., and the International Transporter Consortium. 2013. Intracellular drug concentrations and transporters: Measurement, modeling, and implications for the liver. Clin. Pharmacol. Ther. 94:126‐141.
  Cui, Y., König, J., and Keppler, D. 2001. Vectorial transport by double‐transfected cells expressing the human uptake transporter SLC21A8 and the apical export pump ABCC2. Mol. Pharmacol. 60:934‐943.
  Dawson, S., Stahl, S., Paul, N., Barber, J., and Kenna, J.G. 2012. In vitro inhibition of the bile salt export pump correlates with risk of cholestatic drug‐induced liver injury in humans. Drug Metab. Dispos. 40:130‐138.
  De Bruyn, T., Chatterjee, S., Fattah, S., Keemink, J., Nicolaï, J., Augustijns, P., and Annaert, P. 2013. Sandwich‐cultured hepatocytes: Utility for in vitro exploration of hepatobiliary drug disposition and drug‐induced hepatotoxicity. Expert Opin. Drug Metab. Toxicol. 9:589‐616.
  de Waart, D.R., Häusler, S., Vlaming, M.L.H., Kunne, C., Hänggi, E., Gruss, H.‐J., Oude Elferink, R.P.J., and Stieger, B. 2010. Hepatic transport mechanisms of Cholyl‐L‐Lysyl‐Fluorescein. J. Pharmacol. Exp. Ther. 334:78‐86.
  Dykens, J.A. and Will, Y. 2007. The significance of mitochondrial toxicity testing in drug development. Drug Discov. Today 12:777‐785.
  European Medicine Agency. 2012. European Medicine Agency Committee for Human Medicinal Products (CHMP) Guideline on the Investigation of Drug Interactions CPMP/EWP/560/95/Rev. 1 Corr. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129606.pdf
  Fahrmayr, C., König, J., Auge, D., Mieth, M., and Fromm, M.F. 2012. Identification of drugs and drug metabolites as substrates of multidrug resistance protein 2 (MRP2) using triple‐transfected MDCK‐OATP1B1‐UGT1A1‐MRP2 cells. Br. J. Pharmacol. 165:1836‐1847.
  Fahrmayr, C., König, J., Auge, D., Mieth, M., Münch, K., Segrestaa, J., Pfeifer, T., Treiber, A., and Fromm, M. 2013. Phase I and II metabolism and MRP2‐mediated export of bosentan in a MDCKII‐OATP1B1‐CYP3A4‐UGT1A1‐MRP2 quadruple‐transfected cell line. Br. J. Pharmacol. 169:21‐33.
  Fattinger, K., Funk, C., Pantze, M., Weber, C., Reichen, J., Stieger, B., and Meier, P.J. 2001. The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: A potential mechanism for hepatic adverse reactions. Clin. Pharmacol. Ther. 69:223‐231.
  Ferrigno, A., Richelmi, P., and Vairetti, M. 2013. Troubleshooting and improving the mouse and rat isolated perfused liver preparation. J. Pharmacol. Toxicol. Methods 67:107‐114.
  Fouassier, L., Kinnman, N., Lefèvre, G., Lasnier, E., Rey, C., Poupon, R., Elferink, R.P., and Housset, C. 2002. Contribution of mrp2 in alterations of canalicular bile formation by the endothelin antagonist bosentan. J. Hepatol. 37:184‐191.
  Funk, C., Pantze, M., Jehle, L., Ponelle, C., Scheuermann, G., Lazendic, M., and Gasser, R. 2001. Troglitazone‐induced intrahepatic cholestasis by an interference with the hepatobiliary export of bile acids in male and female rats. Correlation with the gender difference in troglitazone sulfate formation and the inhibition of the canalicular bile salt export pump (Bsep) by troglitazone and troglitazone sulfate. Toxicology 167:83‐98.
  Geenen, S., Taylor, P.N., Snoep, J.L., Wilson, I.D., Kenna, J.G., and Westerhoff, H.V. 2012. Systems biology tools for toxicology. Arch. Toxicol. 86:1251‐1271.
  Gerk, P.M. and Vore, M. 2002. Regulation of expression of the multidrug resistance‐associated protein 2 (MRP2) and its role in drug disposition. J. Pharmacol. Exp. Ther. 302:407‐415.
  Ghibellini, G., Leslie, E.M., and Brouwer, K.L. 2006 Methods to evaluate biliary excretion of drugs in humans: An updated review. Mol. Pharm. 3:198‐211.
  Gonzalez, F.J. 2012. Nuclear receptor control of enterohepatic circulation. Compr. Physiol. 2:2811‐2828.
  Grime, K., Webborn, P.J., and Riley, R.J. 2008. Functional consequences of active hepatic uptake on cytochrome P450 inhibition in rat and human hepatocytes. Drug Metab. Dispos. 36:1670‐1678.
  Gurtovenko, A.A. and Anwar J. 2007. Modulating the structure and properties of cell membranes: The molecular mechanism of action of dimethyl sulfoxide. J. Phys. Chem. B 111:10453‐10460.
  Herédi‐Szabó, K., Kis, E., and Krajcsi, P. 2012. The vesicular transport assay: Validated in vitro methods to study drug‐mediated inhibition of canalicular efflux transporters ABCB11/BSEP and ABCC2/MRP2. Curr. Protoc. Toxicol. 54:23.4.1‐23.4.15.
  Hillgren, K.M., Keppler, D., Zur, A.A., Giacomini, K.M., Stieger, B., Cass, C.E., and Zhang, L. 2013. Emerging transporters of clinical importance: An update from the international transporter consortium. Clin. Pharmacol. Ther. 94:52‐63.
  Hofmann, A.F. and Hagey, L.R. 2008 Bile acids: Chemistry, pathochemistry, biology, pathobiology, and therapeutics. Cell Mol. Life Sci. 65:2461‐2483.
  Hopwood, J., Summers, C., Pognan, F., Barrett, G., Jones, K., Laine, R., and Kenna, G. 2006. A novel method for quantification of canalicular transporter inhibition in primary rat hepatocyte sandwich cultures. Toxicology 226:66‐67.
  Kaplowitz, N. and DeLeve, L. 2013. Drug‐Induced Liver Injury. 3rd edn, Intra Healthcare, New York.
  Kenna, J.G., Stahl, S.H., and Noeske, T. 2014. Strategies for minimisation of the cholestatic liver injury liability posed by drug‐induced bile salt export pump (BSEP) inhibition. In Topics in Medicinal Chemistry. Springer, In press. http://rd.springer.com/chapter/10.1007/7355_2013_30#.
  Kis, E., Ioja, E., Nagy, T., Szente, L., Herédi‐Szabó, K., and Krajcsi, P. 2009a. Effect of membrane cholesterol on BSEP/Bsep activity: species specificity studies for substrates and inhibitors. Drug Metab. Dispos. 37:1878‐1886.
  Kis, E., Rajnai, Z., Ioja, E., Herédi Szabó, K., Nagy, T., Méhn, D., and Krajcsi, P. 2009b. Mouse Bsep ATPase assay: A nonradioactive tool for assessment of the cholestatic potential of drugs. J. Biomol. Screen. 14:10‐15.
  Kola, I. and Landis, J. 2004, Can the pharmaceutical industry reduce attrition rates? Nat. Rev. Drug. Discov. 3:711‐715.
  Kostrubsky, V.E., Strom, S.C., Hanson, J., Urda, E., Rose, K., Burliegh, J., Zocharski, P., Cai, H., Sinclair, J.F., and Sahi, J. 2003. Evaluation of hepatotoxic potential of drugs by inhibition of bile‐acid transport in cultured primary human hepatocytes and intact rats. Toxicol. Sci. 76:220‐228.
  Kostrubsky, S.E., Strom, S.C., Kalgutkar, A.S., Kulkarni, S., Atherton, J., Mireles, R., Feng, B., Kubik, R., Hanson, J., Urda, E., and Mutlib, A.E. 2006. Inhibition of hepatobiliary transport as a predictive method for clinical hepatotoxicity of nefazodone. Toxicol. Sci. 90:451‐459.
  Kroker, R., Anwer, M.S., and Hegner, D. 1978. The interaction of rifamycin SV with hepatic transport of taurocholic acid in the isolated perfused rat liver. Naunyn Schmiedebergs Arch. Pharmacol. 302:323‐327.
  Kullak‐Ublick, G.A., Stieger, B., and Meier, P.J. 2004. Enterohepatic bile salt transporters in normal physiology and liver disease. Gastroenterology 126:322‐342.
  Lam, P., Soroka, C.J., and Boyer, J.L. 2010. The bile salt export pump: Clinical and experimental aspects of genetic and acquired cholestatic liver disease. Semin. Liver Dis. 30:125‐133.
  LeCluyse, E.L. 2001. Human hepatocyte culture systems for the in vitro evaluation of cytochrome P450 expression and regulation. Eur. J. Pharm. Sci. 13:343‐368.
  Liu, X., Chism, J.P., LeCluyse, E.L., Brouwer, K.R., and Brouwer, K.L. 1999. Correlation of biliary excretion in sandwich‐cultured rat hepatocytes and in vivo in rats. Drug Metab. Dispos. 27:637‐644.
  Marshall, R.W., Moreno, O.M., and Brodie, D.A. 1964. Chronic bile duct cannulation in the dog. J. Appl. Physiol. 19:1191‐1192.
  Merle‐Melet, M., Bresler, L., Didelot, J.P., Jehl, F., Gerard, A., and Boissel, P. 1994. A surgical model for studying biliary excretion of drugs in the awake micropig yucatan. J. Exp. Anim. Sci. 36:201‐208.
  Meszaros, J., Nimmerfall, F., Rosenthaler, J., and Weber, H. 1975. Permanent bile duct cannulation in the monkey. A model for studying intestinal absorption. Eur. J. Pharmacol. 32:233‐242.
  Milkiewicz, P., Baiocchi, L., Mills, C.O., Ahmed, M., Khalaf, H., Keogh, A., Baker, J., and Elias, E. 1997. Plasma clearance of cholyl‐lysyl‐fluorescein: A pilot study in humans. J. Hepatol. 27:1106‐1109.
  Mita, S., Suzuki, H., Akita, H., Hayashi, H., Onuki, R., Hofmann, A.F., and Sugiyama, Y. 2006a. Vectorial transport of unconjugated and conjugated bile salts by monolayers of LLC‐PK1 cells doubly transfected with human NTCP and BSEP or with rat Ntcp and Bsep. Am. J. Physiol. Gastrointest. Liver Physiol. 290:G550‐556.
  Mita, S., Suzuki, H., Akita, H., Hayashi, H., Onuki, R., Hofmann, A.F., and Sugiyama, Y. 2006b. Inhibition of bile acid transport across Na+/taurocholate cotransporting polypeptide (SLC10A1) and bile salt export pump (ABCB 11)‐coexpressing LLC‐PK1 cells by cholestasis‐inducing drugs. Drug Metab. Dispos. 34:1575‐1581.
  Morgan, R.E., Trauner, M., van Staden, C.J., Lee, P.H., Ramachandran, B., Eschenberg, M., Afshari, C.A., Qualls, C.W. Jr, Lightfoot‐Dunn, R., and Hamadeh, H.K. 2010. Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol. Sci. 118:485‐500.
  Morgan, R.E., van Staden, C.J., Chen, Y., Kalyanaraman, N., Kalanzi, J., Dunn, R.T. 2nd, Afshari, C.A., and Hamadeh, H.K. 2013. A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. Toxicol. Sci. 136:216‐241.
  Nakanishi, T., Shibue, Y., Fukuyama, Y., Yoshida, K., Fukuda, H., Shirasaka, Y., and Ikumi, T. 2011. Quantitative time‐lapse imaging‐based analysis of drug‐drug interaction mediated by hepatobiliary transporter, multidrug resistance‐associated protein 2, in sandwich‐cultured rat hepatocytes. Drug Metab. Dispos. 39:984‐991.
  Pachkoria, K., Lucena, M.I., Molokhia, M., Cueto, R., Carballo, A.S., Carvajal, A., and Andrade, R.J. 2007. Genetic and molecular factors in drug‐induced liver injury: A review. Curr. Drug Saf. 2:97‐112.
  Park, B.K., Boobis, A., Clarke, S., Goldring, C.E., Jones, D., Kenna, J.G., Lambert, C., Laverty, H.G., Naisbitt, D.J., Nelson, S., Nicoll‐Griffith, D.A., Obach, R.S., Routledge, P., Smith, D.A., Tweedie, D.J., Vermeulen, N., Williams, D.P., Wilson, I.D., and Baillie, T.A. 2011. Managing the challenge of chemically reactive metabolites in drug development. Nat. Rev. Drug. Discov. 10:292‐306.
  Preininger, K., Stingl, H., Englisch, R., Furnsinn, C., Graf, J., Waldhausl, W., and Roden, M. 1999. Acute troglitazone action in isolated perfused rat liver. Br. J. Pharmacol. 126:372‐378.
  Saito, H., Osumi, M., Hirano, H., Shin, W., Nakamura, R., and Ishikawa, T. 2009. Technical pitfalls and improvements for high‐speed screening and QSAR analysis to predict inhibitors of the human bile salt export pump (ABCB11/BSEP). AAPS J. 11:581‐589.
  Stieger, B., Fattinger, K., Madon, J., Kullak‐Ublick, G.A., and Meier, P.J. 2000. Drug‐ and estrogen‐induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver. Gastroenterology 118:422‐430.
  Stieger, B., Meier, Y., and Meier, P.J. 2007. The bile salt export pump. Pflugers Arch. 453:611‐620.
  Strautnieks, S.S., Bull, L.N., Knisely, A.S., Kocoshis, S.A., Dahl, N., Arnell, H., Sokal, E., Dahan, K., Childs, S., Ling, V., Tanner, M.S., Kagalwalla, A.F., Németh, A., Pawlowska, J., Baker, A., Mieli‐Vergani, G., Freimer, N.B., Gardiner, R.M., and Thompson, R.J. 1998. A gene encoding a liver‐specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nat. Genet. 20:233‐238.
  Swift, B., Pfeifer, N.D., and Brouwer, K.L. 2010. Sandwich‐cultured hepatocytes: An in vitro model to evaluate hepatobiliary transporter‐based drug interactions and hepatotoxicity. Drug Metab. Rev.. 42:446‐471.
  Thompson, R.A., Isin, E.M., Li, Y., Weaver, R., Weidolf, L., Wilson, I., Claesson, A., Page, K., Dolgos, H., and Kenna, J.G. 2011. Risk assessment and mitigation strategies for reactive metabolites in drug discovery and development. Chem. Biol. Interact. 192:65‐71.
  Thompson, R.A., Isin, E,M., Li, Y., Weidolf, L., Page, K., Wilson, I., Swallow, S., Middleton, B., Stahl, S., Foster, A.J., Dolgos, H., Weaver, R., and Kenna, J.G. 2012. In vitro approach to assess the potential for risk of idiosyncratic adverse reactions caused by candidate drugs. Chem. Res. Toxicol. 25:1616‐1632.
  Ulloa, J.L., Stahl, S., Yates, J., Woodhouse, N., Kenna, J.G., Jones, H.B., Waterton, J.C., and Hockings, P.D. 2013. Assessment of gadoxetate DCE‐MRI as a biomarker of hepatobiliary transporter inhibition. NMR Biomed. 26:1258‐1270.
  van Staden, C.J., Morgan, R.E., Ramachandran, B., Chen, Y., Lee, P.H., and Hamadeh, H.K. 2012. Membrane vesicle ABC transporter assays for drug safety assessment. Curr. Protoc. Toxicol. 54:23.5.1‐23.5.24.
  van Wijk, H., Donachie, P., Mann, D.L., McMahon, H., and Robb, D. 2001. A novel bile duct cannulation method with tail cuff exteriorization allowing continuous intravenous infusion and enterohepatic recirculation in the unrestrained rat. Lab. Anim. 35:325‐333.
  Wang, Y.M. and Reuning, R.H. 1994. A comparison of two surgical techniques for preparation of rats with chronic bile duct cannulae for the investigation of enterohepatic circulation. Lab. Anim. Sci. 44:479‐485.
  Warner, D.J., Chen, H., Cantin, L.D., Kenna, J.G., Stahl, S., Walker, C.L., and Noeske, T. 2012. 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. 40:2332‐2341.
  West, W.L., Cheatham, L.R., Gaillard, E.T., and Wright, M. 2002. A chronic bile duct and intravenous cannulation model in conscious rabbits for pharmacokinetic studies. J. Invest. Surg. 15:81‐89.
  Yamaguchi, K., Murai, T., Yabuuchi, H., Hui, S.P., and Kurosawa, T. 2010. Measurement of bile salt export pump transport activities using a fluorescent bile acid derivative. Drug. Metab. Pharmacokinet. 25:214‐219.
  Yamazaki, M., Miyake, M., Sato, H., Masutomi, N., Tsutsui, N., Adam, K.P., Alexander, D.C., Lawton, K.A., Milburn, M.V., Ryals, J.A., Wulff, J.E., and Guo, L. 2013. Perturbation of bile acid homeostasis is an early pathogenesis event of drug induced liver injury in rats. Toxicol. Appl. Pharmacol. 268:79‐89.
  Yoshikado, T., Takada, T., Yamamoto, H., Tan, J.K., Ito, K., Santa, T., and Suzuki, H. 2013. Ticlopidine, a cholestatic liver injury‐inducible drug, causes dysfunction of bile formation via diminished biliary secretion of phospholipids: Involvement of biliary‐excreted glutathione‐conjugated ticlopidine metabolites. Mol. Pharmacol. 83:552‐562.
  Zamek‐Gliszczynski, M.J., Xiong, H., Patel, N.J., Turncliff, R.Z., Pollack, G.M., and Brouwer, K.L. 2003. Pharmacokinetics of 5 (and 6)‐carboxy‐2,7‐dichlorofluorescein and its diacetate promoiety in the liver. J. Pharmacol. Exp. Ther. 304:801‐809.
  Zhang, Y., Li, F., Patterson, A.D., Wang, Y., Krausz, K.W., Neale, G., Thomas, S., Nachagari, D., Vogel, P., Vore, M., Gonzalez, F.J., and Schuetz, J.D. 2012. Abcb11 deficiency induces cholestasis coupled to impaired β‐fatty acid oxidation in mice. J. Biol. Chem. 287:24784‐24794.
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