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

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.

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

“…Plasma bile acid concentrations may also be evaluated in humans and so can be used to aid human safety evaluation during clinical trials. It has been proposed that plasma bile acid concentrations should be evaluated in vivo, in preclinical test species, prior to progression from discovery of compounds that exhibit in vitro BSEP inhibition IC 50 <300 μM (Kenna et al, 2014). It is important to evaluate and interpret data on plasma bile acid concentrations alongside standard markers of liver dysfunction, in order to take account of possible non BSEP-related effects that might arise as a secondary consequence of liver damage.…”

“…It is important to evaluate and interpret data on plasma bile acid concentrations alongside standard markers of liver dysfunction, in order to take account of possible non BSEP-related effects that might arise as a secondary consequence of liver damage. A decision tree, which summarizes this proposed workflow, has been described recently (see Kenna et al, 2014).…”