Skip to main content
SpringerLink
Log in

Strategies for Minimisation of the Cholestatic Liver Injury Liability Posed by Drug-Induced Bile Salt Export Pump (BSEP) Inhibition

  • Chapter
  • First Online:
Book cover Tactics in Contemporary Drug Design

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 9))

  • 2834 Accesses

Abstract

Hepatobiliary uptake and efflux transporter proteins play key roles in the formation of bile, which is a vital function of the liver. The ATP-dependent bile salt export pump (BSEP) excretes bile salts from hepatocytes into bile. Inherited BSEP mutations in humans cause intrahepatic accumulation of bile salts, which results in cholestatic liver injury. Furthermore, inhibition of BSEP activity is considered one of a number of key initiating mechanisms by which drugs may cause liver injury (drug-induced liver injury, DILI) in the human population. DILI is an important cause of serious drug-induced illness and is a leading cause of drug attrition during development and of drug withdrawal and restrictive labelling post-marketing. In this chapter we summarise the evidence that BSEP inhibition is a drug-related DILI risk factor, we describe experimental approaches (in silico, in vitro and in vivo) which may be used to predict and quantify this process during drug discovery and development and we discuss data interpretation. We also outline an approach by which assessment of BSEP inhibition in drug discovery can be used to reduce the likelihood that DILI may arise during development. In addition, we consider the current state of computational predictive modelling of BSEP inhibition and discuss the influence of physicochemical parameters.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

Abbreviations

ABC:

ATP-binding cassette

ALT:

Alanine aminotransferase

BCRP:

Breast cancer resistance protein

BRIC2:

Benign recurrent intrahepatic cholestasis type 2

BSEP/Bsep:

Bile salt export pump

CDF:

5(6)-Carboxy-2′,7′-dichlorofluorescein

CLF:

Cholyllysylfluorescein

DILI:

Drug-induced liver injury

IADR:

Idiosyncratic adverse drug reaction

ICP:

Intrahepatic cholestasis of pregnancy

MDCK:

Madin–Darby canine kidney

MDR:

Multidrug resistance

MRP:

Multidrug resistance-associated protein 2

NTCP:

Sodium taurocholate co-transporting polypeptide

OATP:

Organic anion transporting polypeptide

OPLS-DA:

Orthogonal partial least-squares projection to latent structures discriminant analysis

P-gp:

P-glycoprotein, ABCB1

PFIC2:

Progressive familial intrahepatic cholestasis type 2

QSAR:

Quantitative structure–activity relationship

SCH:

Sandwich-cultured hepatocytes

SLC:

Solute carrier

TAP:

Transporter associated with antigen processing

References

  1. Lam P, Soroka CJ, Boyer JL (2010) The bile salt export pump: clinical and experimental aspects of genetic and acquired cholestatic liver disease. Semin Liver Dis 30:125–133

    CAS  Google Scholar 

  2. Cai SY, Wang L, Ballatori N, Boyer JL (2001) Bile salt export pump is highly conserved during vertebrate evolution and its expression is inhibited by PFIC type II mutations. Am J Physiol Gastrointest Liver Physiol 281:G316–G322

    CAS  Google Scholar 

  3. Hofmann AF (2004) Bile composition. In: Johnson L (ed) Encyclopedia of gastroenterology. Elsevier, New York, pp 176–184, http://dx.doi.org/10.1016/B0-12-386860-2/00063-0

    Google Scholar 

  4. Gerk PM, 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

    CAS  Google Scholar 

  5. Zhou SF (2008) Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition. Xenobiotica 38:802–832

    CAS  Google Scholar 

  6. Oude Elferink RPJ, Paulusma CC (2007) Function and pathophysiological importance of ABCB4 (MDR3 P-glycoprotein). Pflugers Arch 453:601–610

    CAS  Google Scholar 

  7. Hofmann AF, Hagey LR (2008) Bile acids: chemistry, pathochemistry, biology, pathobiology, and therapeutics. Cell Mol Life Sci 65:2461–2483

    CAS  Google Scholar 

  8. Kullak-Ublick GA, Stieger B, Meier PJ (2004) Enterohepatic bile salt transporters in normal physiology and liver disease. Gastroenterology 126:322–342

    CAS  Google Scholar 

  9. Gonzalez FJ (2012) Nuclear receptor control of enterohepatic circulation. Compr Physiol 2:2811–2828

    Google Scholar 

  10. Strautnieks SS, Bull LN, Knisely AS, Kocoshis SA, Dahl N, Arnell H, Sokal E, Dahan K, Childs S, Ling V, Tanner MS, Kagalwalla AF, Németh A, Pawlowska J, Baker A, Mieli-Vergani G, Freimer NB, Gardiner RM, Thompson RJ (1998) A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nat Genet 20:233–238

    CAS  Google Scholar 

  11. Byrne JA, Strautnieks SS, Ihrke G, Pagani F, Knisely AS, Linton KJ, Mieli-Vergani G, Thompson RJ (2009) Missense mutations and single nucleotide polymorphisms in ABCB11 impair bile salt export pump processing and function or disrupt pre-messenger RNA splicing. Hepatology 49:553–567

    CAS  Google Scholar 

  12. Ho RH, Leake BF, Kilkenny DM, Meyer Zu Schwabedissen HE, Glaeser H, Kroetz DL, Kim RB (2010) Polymorphic variants in the human bile salt export pump (BSEP; ABCB11): functional characterization and interindividual variability. Pharmacogenet Genomics 20:45–57

    CAS  Google Scholar 

  13. Perez MJ, Briz O (2009) Bile-acid-induced cell injury and protection. World J Gastroenterol 15:1677–1689

    CAS  Google Scholar 

  14. Noe J, Kullak-Ublick GA, Jochum W, Stieger B, Kerb R, Haberl M, Müllhaupt B, Meier PJ, Pauli-Magnus C (2005) Impaired expression and function of the bile salt export pump due to three novel ABCB11 mutations in intrahepatic cholestasis. J Hepatol 43:536–543

    CAS  Google Scholar 

  15. Stieger B, Meier Y, Meier PJ (2007) The bile salt export pump. Pflugers Arch 453:611–620

    CAS  Google Scholar 

  16. Lam P, Pearson CL, Soroka CJ, Xu S, Mennone A, Boyer JL (2007) Levels of plasma membrane expression in progressive and benign mutations of the bile salt export pump (Bsep/Abcb11) correlate with severity of cholestatic diseases. Am J Physiol Cell Physiol 293:C1709–C1716

    CAS  Google Scholar 

  17. Kagawa T, Watanabe N, Mochizuki K, Numari A, Ikeno Y, Itoh J, Tanaka H, Arias IM, Mine T (2008) Phenotypic differences in PFIC2 and BRIC2 correlate with protein stability of mutant Bsep and impaired taurocholate secretion in MDCK II cells. Am J Physiol Gastrointest Liver Physiol 294:G58–G67

    CAS  Google Scholar 

  18. Wang R, Salem M, Yousef IM, Tuchweber B, Lam P, Childs SJ, Helgason CD, Ackerley C, Phillips MJ, Ling V (2001) Targeted inactivation of sister of P-glycoprotein gene (spgp) in mice results in nonprogressive but persistent intrahepatic cholestasis. Proc Natl Acad Sci U S A 98:2011–2016

    CAS  Google Scholar 

  19. Wang R, Lam P, Liu L, Forrest D, Yousef IM, Mignault D, Phillips MJ, Ling V (2003) Severe cholestasis induced by cholic acid feeding in knockout mice of sister of P-glycoprotein. Hepatology 38:1489–1499

    CAS  Google Scholar 

  20. Wang R, Chen HL, Liu L, Sheps JA, Phillips MJ, Ling V (2009) Compensatory role of P-glycoproteins in knockout mice lacking the bile salt export pump. Hepatology 50:948–956

    CAS  Google Scholar 

  21. Zhang Y, Li F, Patterson AD, Wang Y, Krausz KW, Neale G, Thomas S, Nachagari D, Vogel P, Vore M, Gonzalez FJ, Schuetz JD (2012) Abcb11 deficiency induces cholestasis coupled to impaired β-fatty acid oxidation in mice. J Biol Chem 287:24784–24794

    CAS  Google Scholar 

  22. Greaves P, Williams A, Eve M (2004) First dose of potential new medicines to humans: how animals help. Nat Rev Drug Discov 3:226–236

    CAS  Google Scholar 

  23. Kaplowitz N, DeLeve L (2013) Drug-induced liver injury, 3rd edn. Intra Healthcare, New York

    Google Scholar 

  24. Abboud G, Kaplowitz N (2007) Drug-induced liver injury. Drug Saf 30:277–294

    CAS  Google Scholar 

  25. Kola I, Landis J (2004) Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 3:711–715

    CAS  Google Scholar 

  26. Dykens JA, Will Y (2007) The significance of mitochondrial toxicity testing in drug development. Drug Discov Today 12:777–785

    CAS  Google Scholar 

  27. Greer ML, Barber J, Eakins J, Kenna JG (2010) Cell-based approaches for evaluation of drug-induced liver injury. Toxicology 268:125–131

    CAS  Google Scholar 

  28. Roth RA, Ganey PE (2010) Intrinsic versus idiosyncratic drug-induced hepatotoxicity – two villains or one? J Pharmacol Exp Ther 332:692–697

    CAS  Google Scholar 

  29. Thompson RA, Isin EM, Li Y, Weaver R, Weidolf L, Wilson I, Claesson A, Page K, Dolgos H, Kenna JG (2011) Risk assessment and mitigation strategies for reactive metabolites in drug discovery and development. Chem Biol Interact 192:65–71

    CAS  Google Scholar 

  30. Pachkoria K, Lucena MI, Molokhia M, Cueto R, Carballo AS, Carvajal A, Andrade RJ (2007) Genetic and molecular factors in drug-induced liver injury: a review. Curr Drug Saf 2:97–112

    CAS  Google Scholar 

  31. Daly AK, Day CP (2012) Genetic association studies in drug-induced liver injury. Drug Metab Rev 44:116–126

    CAS  Google Scholar 

  32. Stieger B, Fattinger K, Madon J, Kullak-Ublick GA, Meier PJ (2000) Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver. Gastroenterology 118:422–430

    CAS  Google Scholar 

  33. Fattinger K, Funk C, Pantze M, Weber C, Reichen J, Stieger B, Meier PJ (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

    CAS  Google Scholar 

  34. Funk C, Ponelle C, Scheuermann G, Pantze M (2001) Cholestatic potential of troglitazone as a possible factor contributing to troglitazone-induced hepatotoxicity: in vivo and in vitro interaction at the canalicular bile salt export pump (Bsep) in the rat. Mol Pharmacol 59:627–635

    CAS  Google Scholar 

  35. Noé J, Stieger B, Meier PJ (2002) Functional expression of the canalicular bile salt export pump of human liver. Gastroenterology 123:1659–1666

    Google Scholar 

  36. Byrne JA, Strautnieks SS, Mieli-Vergani G, Higgins CF, Linton KJ, Thompson RJ (2002) The human bile salt export pump: characterization of substrate specificity and identification of inhibitors. Gastroenterology 123:1649–1658

    CAS  Google Scholar 

  37. Horikawa M, Kato Y, Tyson CA, Sugiyama Y (2003) Potential cholestatic activity of various therapeutic agents assessed by bile canalicular membrane vesicles isolated from rats and humans. Drug Metab Pharmacokinet 18:16–22

    Google Scholar 

  38. Hirano H, Kurata A, Onishi Y, Sakurai A, Saito H, Nakagawa H, Nagakura M, Tarui S, Kanamori Y, Kitajima M, Ishikawa T (2006) High-speed screening and QSAR analysis of human ATP-binding cassette transporter ABCB11 (bile salt export pump) to predict drug-induced intrahepatic cholestasis. Mol Pharm 3:252–265

    CAS  Google Scholar 

  39. Mano Y, Usui T, Kamimura H (2007) Effects of bosentan, an endothelin receptor antagonist, on bile salt export pump and multidrug resistance-associated protein 2. Biopharm Drug Dispos 28:13–18

    CAS  Google Scholar 

  40. Yabuuchi H, Tanaka K, Maeda M, Takemura M, Oka M, Ohashi R, Tamai I (2008) Cloning of the dog bile salt export pump (BSEP; ABCB11) and functional comparison with the human and rat proteins. Biopharm Drug Dispos 29:441–448

    CAS  Google Scholar 

  41. Kis E, Rajnai Z, Ioja E, Herédi Szabó K, Nagy T, Méhn D, Krajcsi P (2009) Mouse Bsep ATPase assay: a nonradioactive tool for assessment of the cholestatic potential of drugs. J Biomol Screen 14:10–15

    CAS  Google Scholar 

  42. Morgan RE, Trauner M, van Staden CJ, Lee PH, Ramachandran B, Eschenberg M, Afshari CA, Qualls CW Jr, Lightfoot-Dunn R, Hamadeh HK (2010) Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol Sci 118:485–500

    CAS  Google Scholar 

  43. Dawson S, Stahl S, Paul N, Barber J, Kenna JG (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

    CAS  Google Scholar 

  44. Kostrubsky VE, Strom SC, Hanson J, Urda E, Rose K, Burliegh J, Zocharski P, Cai H, Sinclair JF, 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

    CAS  Google Scholar 

  45. Swift B, Pfeifer ND, Brouwer KL (2010) Sandwich-cultured hepatocytes: an in vitro model to evaluate hepatobiliary transporter-based drug interactions and hepatotoxicity. Drug Metab Rev 42:446–471

    CAS  Google Scholar 

  46. Mita S, Suzuki H, Akita H, Stieger B, Meier PJ, Hofmann AF, Sugiyama Y (2005) Vectorial transport of bile salts across MDCK cells expressing both rat Na + −taurocholate cotransporting polypeptide and rat bile salt export pump. Am J Physiol Gastrointest Liver Physiol 288:G159–G167

    CAS  Google Scholar 

  47. Herédi-Szabó K, Kis E, 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 Chapter 23:Unit 23.4

    Google Scholar 

  48. Saito H, Osumi M, Hirano H, Shin W, Nakamura R, 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

    CAS  Google Scholar 

  49. van Staden CJ, Morgan RE, Ramachandran B, Chen Y, Lee PH, Hamadeh HK (2012) Membrane vesicle ABC transporter assays for drug safety assessment. Curr Protoc Toxicol Chapter 23:Unit 23.5

    Google Scholar 

  50. Warner DJ, Chen H, Cantin LD, Kenna JG, Stahl S, Walker CL, 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

    CAS  Google Scholar 

  51. Karlsson JE, Heddle C, Rozkov A, Rotticci-Mulder J, Tuvesson O, Hilgendorf C, Andersson TB (2010) High-activity P-glycoprotein, multidrug resistance protein 2, and breast cancer resistance protein membrane vesicles prepared from transiently transfected human embryonic kidney 293-Epstein-Barr virus nuclear antigen cells. Drug Metab Dispos 38:705–714

    CAS  Google Scholar 

  52. Kis E, Ioja E, Nagy T, Szente L, Herédi-Szabó K, Krajcsi P (2009) Effect of membrane cholesterol on BSEP/Bsep activity: species specificity studies for substrates and inhibitors. Drug Metab Dispos 37:1878–1886

    CAS  Google Scholar 

  53. Elsby R, Smith V, Fox L, Stresser D, Butters C, Sharma P, Surry DD (2011) Validation of membrane vesicle-based breast cancer resistance protein and multidrug resistance protein 2 assays to assess drug transport and the potential for drug-drug interaction to support regulatory submissions. Xenobiotica 41:764–783

    CAS  Google Scholar 

  54. Meier PJ, Boyer JL (1990) Preparation of basolateral (sinusoidal) and canalicular plasma membrane vesicles for the study of hepatic transport processes. Methods Enzymol 192:534–545

    CAS  Google Scholar 

  55. Pauli-Magnus C, Meier PJ, Stieger B (2010) Genetic determinants of drug-induced cholestasis and intrahepatic cholestasis of pregnancy. Semin Liver Dis 30:147–159

    CAS  Google Scholar 

  56. Hirano M, Maeda K, Hayashi H, Kusuhara H, Sugiyama Y (2005) Bile salt export pump (BSEP/ABCB11) can transport a nonbile acid substrate, pravastatin. J Pharmacol Exp Ther 314:876–882

    CAS  Google Scholar 

  57. Lecureur V, Sun D, Hargrove P, Schuetz EG, Kim RB, Lan LB, Schuetz JD (2000) Cloning and expression of murine sister of P-glycoprotein reveals a more discriminating transporter than MDR1/P-glycoprotein. Mol Pharmacol 57:24–35

    CAS  Google Scholar 

  58. Wang L, Soroka CJ, Boyer JL (2002) The role of bile salt export pump mutations in progressive familial intrahepatic cholestasis type II. J Clin Invest 110:965–972

    CAS  Google Scholar 

  59. Hayashi H, Takada T, Suzuki H, Akita H, Sugiyama Y (2005) Two common PFIC2 mutations are associated with the impaired membrane trafficking of BSEP/ABCB11. Hepatology 41:916–924

    CAS  Google Scholar 

  60. Cui Y, König J, 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

    CAS  Google Scholar 

  61. Fahrmayr C, König J, Auge D, Mieth M, Fromm MF (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

    CAS  Google Scholar 

  62. Fahrmayr C, König J, Auge D, Mieth M, Münch K, Segrestaa J, Pfeifer T, Treiber A, 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

    CAS  Google Scholar 

  63. Mita S, Suzuki H, Akita H, Hayashi H, Onuki R, Hofmann AF, Sugiyama Y (2006) 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–G556

    CAS  Google Scholar 

  64. Mita S, Suzuki H, Akita H, Hayashi H, Onuki R, Hofmann AF, Sugiyama Y (2006) 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

    Google Scholar 

  65. De Bruyn T, Chatterjee S, Fattah S, Keemink J, Nicolaï J, Augustijns P, 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

    Google Scholar 

  66. Liu X, Chism JP, LeCluyse EL, Brouwer KR, Brouwer KL (1999) Correlation of biliary excretion in sandwich-cultured rat hepatocytes and in vivo in rats. Drug Metab Dispos 27:637–644

    CAS  Google Scholar 

  67. Chu X, Korzekwa K, Elsby R, Fenner K, Galetin A, Lai Y, Matsson P, Moss A, Nagar S, Rosania GR, Bai JP, Polli JW, Sugiyama Y, Brouwer KL (2013) Intracellular drug concentrations and transporters: measurement, modeling, and implications for the liver. Clin Pharmacol Ther 94:126–141

    CAS  Google Scholar 

  68. Kostrubsky SE, Strom SC, Kalgutkar AS, Kulkarni S, Atherton J, Mireles R, Feng B, Kubik R, Hanson J, Urda E, Mutlib AE (2006) Inhibition of hepatobiliary transport as a predictive method for clinical hepatotoxicity of nefazodone. Toxicol Sci 90:451–459

    CAS  Google Scholar 

  69. Zamek-Gliszczynski MJ, Xiong H, Patel NJ, Turncliff RZ, Pollack GM, Brouwer KL (2003) Pharmacokinetics of 5 (and 6)-carboxy-2,7-dichlorofluorescein and its diacetate promoiety in the liver. J Pharmacol Exp Ther 304:801–809

    CAS  Google Scholar 

  70. Nakanishi T, Shibue Y, Fukuyama Y, Yoshida K, Fukuda H, Shirasaka Y, 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

    CAS  Google Scholar 

  71. Milkiewicz P, Baiocchi L, Mills CO, Ahmed M, Khalaf H, Keogh A, Baker J, Elias E (1997) Plasma clearance of cholyl-lysyl-fluorescein: a pilot study in humans. J Hepatol 27:1106–1109

    CAS  Google Scholar 

  72. Mills CO, Milkiewicz P, Müller M, Roma MG, Havinga R, Coleman R, Kuipers F, Jansen PL, Elias E (1999) Different pathways of canalicular secretion of sulfated and non-sulfated fluorescent bile acids: a study in isolated hepatocyte couplets and TR- rats. J Hepatol 31:678–684

    CAS  Google Scholar 

  73. Hopwood J, Summers C, Pognan F, Barrett G, Jones K, Laine R, Kenna G (2006) A novel method for quantification of canalicular transporter inhibition in primary rat hepatocyte sandwich cultures. Toxicology 226:66–67

    Google Scholar 

  74. de Waart DR, Häusler S, Vlaming MLH, Kunne C, Hänggi E, Gruss H-J, Oude Elferink RPJ, Stieger B (2010) Hepatic transport mechanisms of cholyl-L-lysyl-fluorescein. J Pharmacol Exp Ther 334:78–86

    Google Scholar 

  75. Yamaguchi K, Murai T, Yabuuchi H, Hui SP, Kurosawa T (2010) Measurement of bile salt export pump transport activities using a fluorescent bile acid derivative. Drug Metab Pharmacokinet 25:214–219

    CAS  Google Scholar 

  76. Ferrigno A, Richelmi P, Vairetti M (2013) Troubleshooting and improving the mouse and rat isolated perfused liver preparation. J Pharmacol Toxicol Methods 67:107–114

    CAS  Google Scholar 

  77. Preininger K, Stingl H, Englisch R, Furnsinn C, Graf J, Waldhausl W, Roden M (1999) Acute troglitazone action in isolated perfused rat liver. Br J Pharmacol 126:372–378

    CAS  Google Scholar 

  78. Kroker R, Anwer MS, 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

    CAS  Google Scholar 

  79. Wang YM, Reuning RH (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

    CAS  Google Scholar 

  80. van Wijk H, Donachie P, Mann DL, McMahon H, 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

    Google Scholar 

  81. Marshall RW, Moreno OM, Brodie DA (1964) Chronic bile duct cannulation in the dog. J Appl Physiol 19:1191–1192

    CAS  Google Scholar 

  82. Meszaros J, Nimmerfall F, Rosenthaler J, Weber H (1975) Permanent bile duct cannulation in the monkey. A model for studying intestinal absorption. Eur J Pharmacol 32:233–242

    CAS  Google Scholar 

  83. West WL, Cheatham LR, Gaillard ET, Wright M (2002) A chronic bile duct and intravenous cannulation model in conscious rabbits for pharmacokinetic studies. J Invest Surg 15:81–89

    Google Scholar 

  84. Merle-Melet M, Bresler L, Didelot JP, Jehl F, Gerard A, Boissel P (1994) A surgical model for studying biliary excretion of drugs in the awake micropig yucatan. J Exp Anim Sci 36:201–208

    CAS  Google Scholar 

  85. Ghibellini G, Leslie EM, Brouwer KL (2006) Methods to evaluate biliary excretion of drugs in humans: an updated review. Mol Pharm 3:198–211

    CAS  Google Scholar 

  86. Böhme M, Müller M, Leier I, Jedlitschky G, Keppler D (1994) Cholestasis caused by inhibition of the adenosine triphosphate-dependent bile salt transport in rat liver. Gastroenterology 107:255–265

    Google Scholar 

  87. Fouassier L, Kinnman N, Lefèvre G, Lasnier E, Rey C, Poupon R, Elferink RP, Housset C (2002) Contribution of mrp2 in alterations of canalicular bile formation by the endothelin antagonist bosentan. J Hepatol 37:184–191

    CAS  Google Scholar 

  88. Yoshikado T, Takada T, Yamamoto H, Tan JK, Ito K, Santa T, 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

    CAS  Google Scholar 

  89. Funk C, Pantze M, Jehle L, Ponelle C, Scheuermann G, Lazendic M, 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

    CAS  Google Scholar 

  90. Feng B, Xu JJ, Bi YA, Mireles R, Davidson R, Duignan DB, Campbell S, Kostrubsky VE, Dunn MC, Smith AR, Wang HF (2009) Role of hepatic transporters in the disposition and hepatotoxicity of a HER2 tyrosine kinase inhibitor CP-724,714. Toxicol Sci 108:492–500

    CAS  Google Scholar 

  91. Ulloa JL, Stahl S, Yates J, Woodhouse N, Kenna JG, Jones HB, Waterton JC, Hockings PD (2013) Assessment of gadoxetate DCE-MRI as a biomarker of hepatobiliary transporter inhibition. NMR Biomed 26(10):1258–1270

    CAS  Google Scholar 

  92. Pähler A, Funk C (2008) Drug-induced hepatotoxicity: learning from recent cases of drug attrition. In: Fishbein JC (ed) Advances in Molecular Toxicology, vol 2, 1st edn. Elsevier, Oxford, pp 25–56

    Google Scholar 

  93. Yamazaki M, Miyake M, Sato H, Masutomi N, Tsutsui N, Adam KP, Alexander DC, Lawton KA, Milburn MV, Ryals JA, Wulff JE, 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

    CAS  Google Scholar 

  94. Ito K, Chiba K, Horikawa M, Ishigami M, Mizuno N, Aoki J, Gotoh Y, Iwatsubo T, Kanamitsu S, Kato M, Kawahara I, Niinuma K, Nishino A, Sato N, Tsukamoto Y, Ueda K, Itoh T, Sugiyama Y (2002) Which concentration of the inhibitor should be used to predict in vivo drug interactions from in vitro data? AAPS PharmSci 4:53–60

    Google Scholar 

  95. Grime K, Webborn PJ, Riley RJ (2008) Functional consequences of active hepatic uptake on cytochrome P450 inhibition in rat and human hepatocytes. Drug Metab Dispos 36:1670–1678

    CAS  Google Scholar 

  96. Lee JK, Paine MF, Brouwer KL (2010) Sulindac and its metabolites inhibit multiple transport proteins in rat and human hepatocytes. J Pharmacol Exp Ther 334:410–418

    CAS  Google Scholar 

  97. 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 (2012) In vitro approach to assess the potential for risk of idiosyncratic adverse reactions caused by candidate drugs. Chem Res Toxicol 25:1616–1632

    CAS  Google Scholar 

  98. Hillgren KM, Keppler D, Zur AA, Giacomini KM, Stieger B, Cass CE, Zhang L (2013) Emerging transporters of clinical importance: an update from the International Transporter Consortium. Clin Pharmacol Ther 94:52–63

    CAS  Google Scholar 

  99. European Medicines 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

  100. Nigsch F, Lounkine E, McCarren P, Cornett B, Glick M, Azzaoui K, Urban L, Marc P, Müller A, Hahne F, Heard DJ, Jenkins JL (2011) Computational methods for early predictive safety assessment from biological and chemical data. Expert Opin Drug Metab Toxicol 7:1497–1511

    CAS  Google Scholar 

  101. Fujita T, Hansch C (1967) Analysis of the structure-activity relationship of the sulfonamide drugs using substituent constants. J Med Chem 10:991–1000

    CAS  Google Scholar 

  102. Liu P, Long W (2009) Current mathematical methods used in QSAR/QSPR studies. Int J Mol Sci 10:1978–1998

    CAS  Google Scholar 

  103. Michielan L, Moro S (2010) Pharmaceutical perspectives of nonlinear QSAR strategies. J Chem Inf Model 50:961–978

    CAS  Google Scholar 

  104. Broccatelli F (2012) QSAR models for P-glycoprotein transport based on a highly consistent data set. J Chem Inf Model 52:2462–2470

    CAS  Google Scholar 

  105. Bikadi Z, Hazai I, Malik D, Jemnitz K, Veres Z, Hari P, Ni Z, Loo TW, Clarke DM, Hazai E, Mao Q (2011) Predicting P-glycoprotein-mediated drug transport based on support vector machine and three-dimensional crystal structure of P-glycoprotein. PLoS One 6:e25815, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186768/

    CAS  Google Scholar 

  106. Pedersen JM, Matsson P, Bergström CA, Norinder U, Hoogstraate J, Artursson P (2008) Prediction and identification of drug interactions with the human ATP-binding cassette transporter multidrug-resistance associated protein 2 (MRP2; ABCC2). J Med Chem 51:3275–3287

    CAS  Google Scholar 

  107. Sakurai A, Kurata A, Onishi Y, Hirano H, Ishikawa T (2007) 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 6:71–86

    CAS  Google Scholar 

  108. Carlsson L, Helgee EA, Boyer S (2009) Interpretation of nonlinear QSAR models applied to Ames mutagenicity data. J Chem Inf Model 49:2551–2558

    CAS  Google Scholar 

  109. Stålring J, Almeida PR, Carlsson L, Helgee Ahlberg E, Hasselgren C, Boyer S (2013) Localized heuristic inverse quantitative structure activity relationship with bulk descriptors using numerical gradients. J Chem Inf Model 53(8):2001–2017

    Google Scholar 

  110. Matsson P, Artursson P (2013) Computational prospecting for drug-transporter interactions. Clin Pharmacol Ther 94:30–32

    CAS  Google Scholar 

  111. Wang L, Dong H, Soroka CJ, Wei N, Boyer JL, Hochstrasser M (2008) Degradation of the bile salt export pump at endoplasmic reticulum in progressive familial intrahepatic cholestasis type II (PFIC II). Hepatology 48:1558–1569

    CAS  Google Scholar 

  112. Crocenzi FA, Sánchez Pozzi EJ, Ruiz ML, Zucchetti AE, Roma MG, Mottino AD, Vore M (2010) Ca2+-dependent protein kinase C isoforms are critical to estradiol 17β-D-glucuronide-induced cholestasis in the rat. Hepatology 48:1885–1895

    Google Scholar 

  113. Lam P, Xu S, Soroka CJ, Boyer JL (2012) A C-terminal tyrosine-based motif in the bile salt export pump directs clathrin-dependent endocytosis. Hepatology 55:1901–1911

    CAS  Google Scholar 

  114. Geenen S, Taylor PN, Snoep JL, Wilson ID, Kenna JG, Westerhoff HV (2012) Systems biology tools for toxicology. Arch Toxicol 86:1251–1271

    CAS  Google Scholar 

  115. Bhattacharya S, Shoda LK, Zhang Q, Woods CG, Howell BA, Siler SQ, Woodhead JL, Yang Y, McMullen P, Watkins PB, Andersen ME (2012) Modeling drug- and chemical-induced hepatotoxicity with systems biology approaches. Front Physiol 3:462. doi:10.3389/fphys.2012.00462

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Safety Science Consultant, Macclesfield, UK

    J. Gerry Kenna

  2. DMPK, Drug Safety and Metabolism, AstraZeneca R&D Alderley Park, Macclesfield, Cheshire, UK

    Simone H. Stahl

  3. Discovery Safety, Drug Safety and Metabolism, AstraZeneca R&D Mölndal, Mölndal, Sweden

    Tobias Noeske

Authors
  1. J. Gerry Kenna
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Simone H. Stahl
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tobias Noeske
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. Gerry Kenna .

Editor information

Editors and Affiliations

  1. Bristol-Myers Squibb, Wallingford, Connecticut, USA

    Nicholas A. Meanwell

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Kenna, J.G., Stahl, S.H., Noeske, T. (2013). Strategies for Minimisation of the Cholestatic Liver Injury Liability Posed by Drug-Induced Bile Salt Export Pump (BSEP) Inhibition. In: Meanwell, N. (eds) Tactics in Contemporary Drug Design. Topics in Medicinal Chemistry, vol 9. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7355_2013_30

Download citation

Publish with us

Policies and ethics

Search

Navigation