title: Human drug-induced liver injury severity is highly associated with dual inhibition of liver mitochondrial function and bile salt export pump.
abstract: Drug-induced liver injury (DILI) accounts for 20-40% of all instances of clinical hepatic failure and is a common reason for withdrawal of an approved drug or discontinuation of a potentially new drug from clinical/nonclinical development. Numerous individual risk factors contribute to the susceptibility to human DILI and its severity that are either compound- and/or patient-specific. Compound-specific primary mechanisms linked to DILI include: cytotoxicity, reactive metabolite formation, inhibition of bile salt export pump (BSEP), and mitochondrial dysfunction. Since BSEP is an energy-dependent protein responsible for the efflux of bile acids from hepatocytes, it was hypothesized that humans exposed to drugs that impair both mitochondrial energetics and BSEP functional activity are more sensitive to more severe manifestations of DILI than drugs that only have a single liability factor. As annotated in the United States National Center for Toxicological Research Liver Toxicity Knowledge Base (NCTR-LTKB), the inhibitory properties of 24 Most-DILI-, 28 Less-DILI-, and 20 No-DILI-concern drugs were investigated. Drug potency for inhibiting BSEP or mitochondrial activity was generally correlated across human DILI concern categories. However, drugs with dual potency as mitochondrial and BSEP inhibitors were highly associated with more severe human DILI, more restrictive product safety labeling related to liver injury, and appear more sensitive to the drug exposure (Cmax) where more restrictive labeling occurs.
  
  
  CONCLUSIONS
  These data affirm that severe manifestations of human DILI are multifactorial, highly associated with combinations of drug potency specifically related to known mechanisms of DILI (like mitochondrial and BSEP inhibition), and, along with patient-specific factors, lead to differences in the severity and exposure thresholds associated with clinical DILI.
authors.affiliation: Investigative Toxicology, Drug Safety Research and Development, Pfizer Inc, Groton, CT.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Aleo
authors.forename: Yi
authors.initials: Y
authors.lastname: Luo
authors.forename: Rachel
authors.initials: R
authors.lastname: Swiss
authors.forename: Paul D
authors.initials: PD
authors.lastname: Bonin
authors.forename: David M
authors.initials: DM
authors.lastname: Potter
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Will
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D006801:Humans; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index
chemical_list: C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters