Metabolic, idiosyncratic toxicity of drugs: overview of the hepatic toxicity induced by the anxiolytic, panadiplon

Chemico-biological Interactions
Roger G UlrichE L Sun

Abstract

Preclinical drug safety evaluation studies, typically conducted in two or more animal species, reveal and define dose-dependent toxicities and undesirable effects related to pharmacological mechanism of action. Idiosyncratic toxic responses are often not detected during this phase in development due to their relative rarity in incidence and differences in species sensitivity. This paper reviews and discusses the metabolic idiosyncratic toxicity and species differences observed for the experimental non-benzodiazepine anxiolytic, panadiplon. This compound produced evidence of hepatic toxicity in Phase 1 clinical trial volunteers that was not predicted by rat, dog or monkey preclinical studies. However, subsequent studies in Dutch-belted rabbits revealed a hepatic toxic syndrome consistent with a Reye's Syndrome-like idiosyncratic response. Investigations into the mechanism of toxicity using rabbits and cultured hepatocytes from several species, including human, provided a sketch of the complex pathway required to produce hepatic injury. This pathway includes drug metabolism to a carboxylic acid metabolite (cyclopropane carboxylic acid), inhibition of mitochondrial fatty acid beta-oxidation, and effects on intermediary metabolism ...Continue Reading

References

Jan 1, 1992·Critical Reviews in Toxicology·T J Monks, S S Lau
Jan 1, 1992·Toxicology and Applied Pharmacology·T J MonksD G Graham
Apr 1, 1991·Fundamental and Applied Toxicology : Official Journal of the Society of Toxicology·C A RahnD J Doolittle
Sep 1, 1991·Toxicology and Applied Pharmacology·L J Ruff, E P Brass
Aug 1, 1990·In Vitro Cellular & Developmental Biology : Journal of the Tissue Culture Association·R G UlrichL C Ginsberg
Mar 1, 1991·The Biochemical Journal·K MeldeS Ghisla
Mar 1, 1990·The Journal of Nutrition·E P BrassS P Stabler
Jul 1, 1989·Medical Toxicology and Adverse Drug Experience·J OsterlohD Combest
Jan 1, 1988·Annual Review of Cell Biology·L B Chen
Nov 15, 1985·Archives of Biochemistry and Biophysics·M E Steinhelper, M S Olson
Jul 1, 1985·Gastroenterology·G DananJ P Benhamou
Oct 1, 1985·Archives of Biochemistry and Biophysics·D A OttoG A Cook
Nov 20, 1974·Clinica Chimica Acta; International Journal of Clinical Chemistry·T BöhmerH E Solberg
May 1, 1969·Analytical Biochemistry·J B Allred, D G Guy
Mar 1, 1972·Clinica Chimica Acta; International Journal of Clinical Chemistry·G Cederblad, S Lindstedt
Jul 1, 1983·Metabolism: Clinical and Experimental·D B BuxtonM S Olson
Nov 1, 1984·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·J W KestersonJ M Machinist
Apr 1, 1984·Fundamental and Applied Toxicology : Official Journal of the Society of Toxicology·R G ThurmanJ J Lemasters
Sep 1, 1982·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·H J Zimmerman, K G Ishak
Feb 1, 1980·Proceedings of the National Academy of Sciences of the United States of America·L V JohnsonL B Chen
Jan 1, 1995·Critical Reviews in Toxicology·U A BoelsterliA Kretz-Rommel
Sep 1, 1994·Drug Safety : an International Journal of Medical Toxicology and Drug Experience·M J Rieder
Jul 1, 1994·The American Journal of Physiology·A L NieminenJ J Lemasters
Mar 1, 1994·Chemico-biological Interactions·E P Brass
Sep 1, 1996·Acta Paediatrica·J W HouT R Wang
Sep 11, 1998·The American Journal of Gastroenterology·T R Riley, J P Smith
Oct 17, 1998·Seminars in Liver Disease·W R Treem, R J Sokol

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Citations

Dec 25, 2004·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Michael J LiguoriJeffrey F Waring
Feb 28, 2006·Veterinary Research Communications·P G FerreiraA P Aguas
Sep 9, 2006·Annual Review of Medicine·Roger G Ulrich
Nov 27, 2004·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·James P LuyendykRobert A Roth
Nov 4, 2004·Chemico-biological Interactions·Yi YangJeffrey F Waring
Sep 7, 2011·Drug Metabolism Reviews·Dominique PessayreAbdellah Mansouri
Jul 6, 2011·Critical Reviews in Toxicology·Robert A Roth, Patricia E Ganey
Nov 28, 2006·Expert Opinion on Drug Metabolism & Toxicology·Michael J Liguori, Jeffrey F Waring
Sep 29, 2009·Biomarkers : Biochemical Indicators of Exposure, Response, and Susceptibility to Chemicals·Ulf AnderssonIna Schuppe-Koistinen
Jun 2, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Catherine D TsaltaPeter D Gorycki
Aug 21, 2007·Journal of Computational Chemistry·Maykel Cruz-MonteagudoFernanda Borges
May 4, 2021·RSC Medicinal Chemistry·Matthias R BauerBenjamin C Whitehurst
Mar 19, 2011·Journal of Medicinal Chemistry·Nicholas A Meanwell
Aug 25, 2020·ACS Medicinal Chemistry Letters·James J CrawfordWendy B Young

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