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

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

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.

Keywords

  • Bile acids
  • Bile salt export pump
  • Cholestasis
  • Computational modelling
  • Drug-induced liver injury

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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

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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

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