Interference with Bile Salt Export Pump Function Is a Susceptibility Factor for Human Liver Injury in Drug Development

Abstract

The bile salt export pump (BSEP) is an efflux transporter, driving the elimination of endobiotic and xenobiotic substrates from hepatocytes into the bile. More specifically, it is responsible for the elimination of monovalent, conjugated bile salts, with little or no assistance from other apical transporters. Disruption of BSEP activity through genetic disorders is known to manifest in clinical liver injury such as progressive familial intrahepatic cholestasis type 2. Drug-induced disruption of BSEP is hypothesized to play a role in the development of liver injury for several marketed or withdrawn therapeutics. Unfortunately, preclinical animal models have been poor predictors of the liver injury associated with BSEP interference observed for humans, possibly because of interspecies differences in bile acid composition, differences in hepatobiliary transporter modulation or constitutive expression, as well as other mechanisms. Thus, a BSEP-mediated liver liability may go undetected until the later stages of drug development, such as during clinical trials or even postlicensing. In the absence of a relevant preclinical test system for BSEP-mediated liver injury, the toxicological relevance of available in vitro models to human health rely on the use of benchmark compounds with known clinical outcomes, such as marketed or withdrawn drugs. In this study, membrane vesicles harvested from BSEP-transfected insect cells were used to assess the activity of more than 200 benchmark compounds to thoroughly investigate the relationship between interference with BSEP function and liver injury. The data suggest a relatively strong association between the pharmacological interference with BSEP function and human hepatotoxicity. Although the most accurate translation of risk would incorporate pharmacological potency, pharmacokinetics, clearance mechanisms, tissue distribution, physicochemical properties, indication, and other drug attributes, the additional understanding of a compound's potency for BSEP interference should help to limit or avoid BSEP-related liver liabilities in humans that are not often detected by standard preclinical animal models.

Flagging Drugs That Inhibit the Bile Salt Export Pump

“…Those were therefore not considered as inhibitors. Morgan et al 16 measured the BSEP inhibition activity of 217 compounds to relate them with liver injuries. Compounds with IC 50 below 25 µM were taken as inhibitors, while compounds with IC 50 over 135 µM were taken as non-inhibitors.…”

“…Compounds with IC 50 below 25 µM were taken as inhibitors, while compounds with IC 50 over 135 µM were taken as non-inhibitors. The 25 µM threshold was chosen because, among the compounds that were present both in the training set and in 16 , the equivalent IC 50 in the training set was usually below 10 µM. The chemical structures were retrieved by name from Pubchem Compound (http://www.ncbi.nlm.nih.gov/pccompound).…”

“…Since we used a threshold of 10 µM to define an active in the training set, we count both results as false positives. Tamoxifen and nelfinavir are inconsistently reported with both inhibitor and non-inhibitor activities 8,16,10,13 . This leaves us with 32 compounds that are top ranked and for which we could not find any pharmacological annotation regarding BSEP.…”

Utilizing in vitro transporter data in IVIVE-PBPK: an overview

“…Impaired bile acid export may lead to increased concentrations of liver bile acids, causing hepatocellular apoptosis and/or necrosis. Thus, drugs with the potential to inhibit these transporters can disturb the disposition of both co-administered drugs and bile acid, contributing to the development of cholestatic drug-induced liver injury (DILI) [42,43]. In vitro studies with isolated membrane vesicles have demonstrated an association between DILI and the inhibitory effects of drugs on bile acid efflux transporters [43][44][45].…”

Pharmacogenetics of Drug Transporters in the Enterohepatic Circulation

“…However, BSEP is inhibited by a great variety of drugs and, thus, plays a crucial role in the pathogenesis of drug induced cholestatic liver disease [18,[73][74][75]. MRP3 mediates biliary phospholipid secretion [76], ABCG5/ABCG8 facilitates canalicular cholesterol release [77] and the p-type ATPase ATP8B1 is essential for canalicular bile formation and probably acts as an animophospholipid flipase [78].…”