RRC ID 67791
Author Kenna JG, Stahl SH, Eakins JA, Foster AJ, Andersson LC, Bergare J, Billger M, Elebring M, Elmore CS, Thompson RA.
Title Multiple compound-related adverse properties contribute to liver injury caused by endothelin receptor antagonists.
Journal J Pharmacol Exp Ther
Abstract Drug-induced liver injury has been observed in patients treated with the endothelin receptor antagonists sitaxentan and bosentan, but not following treatment with ambrisentan. The aim of our studies was to assess the possible role of multiple contributory mechanisms in this clinically relevant toxicity. Inhibition of the bile salt export pump (BSEP) and multidrug resistance-associated protein 2 was quantified using membrane vesicle assays. Inhibition of mitochondrial respiration in human liver-derived HuH-7 cells was determined using a Seahorse XF(e96) analyzer. Cytochrome P450 (P450)-independent and P450-mediated cell toxicity was assessed using transfected SV40-T-antigen-immortalized human liver epithelial (THLE) cell lines. Exposure-adjusted assay ratios were calculated by dividing the maximum human drug plasma concentrations by the IC50 or EC50 values obtained in vitro. Covalent binding (CVB) of radiolabeled drugs to human hepatocytes was quantified, and CVB body burdens were calculated by adjusting CVB values for fractional drug turnover in vitro and daily therapeutic dose. Sitaxentan exhibited positive exposure-adjusted signals in all five in vitro assays and a high CVB body burden. Bosentan exhibited a positive exposure-adjusted signal in one assay (BSEP inhibition) and a moderate CVB body burden. Ambrisentan exhibited no positive exposure-adjusted assay signals and a low CVB body burden. These data indicate that multiple mechanisms contribute to the rare, but potentially severe liver injury caused by sitaxentan in humans; provide a plausible rationale for the markedly lower propensity of bosentan to cause liver injury; and highlight the relative safety of ambrisentan.
Volume 352(2)
Pages 281-90
Published 2015-2-1
DOI 10.1124/jpet.114.220491
PII jpet.114.220491
PMID 25467130
MeSH ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors ATP Binding Cassette Transporter, Subfamily B, Member 11 ATP-Binding Cassette Transporters / antagonists & inhibitors Bosentan Cell Line Cell Survival / drug effects Chemical and Drug Induced Liver Injury / etiology* Chemical and Drug Induced Liver Injury / metabolism Cytochrome P-450 Enzyme System / metabolism Dose-Response Relationship, Drug Endothelin Receptor Antagonists / pharmacokinetics Endothelin Receptor Antagonists / toxicity* Epithelial Cells / drug effects Epithelial Cells / metabolism Hepatocytes / drug effects Hepatocytes / metabolism Humans Isoxazoles / pharmacokinetics Isoxazoles / toxicity* Mitochondria / metabolism Molecular Structure Oxygen Consumption / physiology Phenylpropionates / pharmacokinetics Phenylpropionates / toxicity* Pyridazines / pharmacokinetics Pyridazines / toxicity* Sulfonamides / pharmacokinetics Sulfonamides / toxicity* Thiophenes / pharmacokinetics Thiophenes / toxicity*
IF 3.561
Resource
Human and Animal Cells HuH-7