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Title: Liver biomarker and in vitro assessment confirm the hepatic origin of aminotransferase elevations lacking histopathological correlate in beagle dogs treated with GABA{sub A} receptor antagonist NP260

NP260 was designed as a first-in-class selective antagonist of α4-subtype GABA{sub A} receptors that had promising efficacy in animal models of pain, epilepsy, psychosis, and anxiety. However, development of NP260 was complicated following a 28-day safety study in dogs in which pronounced elevations of serum aminotransferase levels were observed, although there was no accompanying histopathological indication of hepatocellular injury. To further investigate the liver effects of NP260, we assayed stored serum samples from the 28-day dog study for liver specific miRNA (miR-122) as well as enzymatic biomarkers glutamate dehydrogenase and sorbitol dehydrogenase, which indicate liver necrosis. Cytotoxicity assessments were conducted in hepatocytes derived from dog, rat, and human liver samples to address the species specificity of the liver response to NP260. All biomarkers, except ALT, returned toward baseline by Day 29 despite continued drug treatment, suggesting adaptation to the initial injury. In vitro analysis of the toxicity potential of NP260 to primary hepatocytes indicated a relative sensitivity of dog > human > rat, which may explain, in part, why the liver effects were not evident in the rodent safety studies. Taken together, the data indicate that a diagnostic biomarker approach, coupled with sensitive in vitro screening strategies, may facilitate interpretationmore » of toxicity potential when an adaptive event masks the underlying toxicity. - Highlights: • NP260 caused ALT elevations in dogs without evidence of hepatocellular injury. • SDH, GLDH, and miRNA-122 elevations occurred, confirming hepatocellular necrosis. • NP260 toxicity is greater in dog and human hepatocytes than in rat hepatocytes. • Species sensitivity may explain why the rodent studies failed to indicate risk. • Diagnostic biomarkers and hepatocyte studies aid interpretation of hepatotoxicity.« less
Authors:
 [1] ;  [2] ;  [3] ;  [4] ;  [5] ;  [6] ; ; ;  [7] ;  [3] ;  [2] ;  [4]
  1. College of Public Health, The University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States)
  2. (United States)
  3. The Hamner-University of North Carolina Institute for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709 (United States)
  4. The Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709 (United States)
  5. College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607 (United States)
  6. QPS, Newark, DE 19711 (United States)
  7. NeuroTherapeutics Pharma, Inc., Chicago, IL 60631 (United States)
Publication Date:
OSTI Identifier:
22439720
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 277; Journal Issue: 2; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BEAGLES; BIOLOGICAL MARKERS; EPILEPSY; IN VITRO; INJURIES; LIVER; LIVER CELLS; NECROSIS; PAIN; RATS; RECEPTORS; SAFETY; SCREENING; SENSITIVITY; SORBITOL; TOXICITY