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

Preclinical drug safety evaluation studies, typically conducted in two or m ore animal species, reveal and define dose-dependent toxicities and undesir able 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 sensitivi ty. This paper reviews and discusses the metabolic idiosyncratic toxicity a nd species differences observed for the experimental non-benzodiazepine anx iolytic, panadiplon. This compound produced evidence of hepatic toxicity in Phase 1 clinical trial volunteers that was not predicted by rat, dog or mo nkey preclinical studies. However, subsequent studies in Dutch-belted rabbi ts revealed a hepatic toxic syndrome consistent with a Reye's Syndrome-like idiosyncratic response. Investigations into the mechanism of toxicity usin g 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 (cy clopropane carboxylic acid), inhibition of mitochondrial fatty acid beta -o xidation. and effects on intermediary metabolism including depletion of gly cogen and disruption of glucose homeostasis. We also provide evidence sugge sting that the carboxylic acid metabolite decreases the availability of liv er CoA and carnitine secondary to the formation of unusual acyl derivatives . Hepatic toxicity could be ameliorated by administration of carnitine, and to a lesser extent by pantothenate. These hepatocellular pathway defects, though not directly resulting in cell death. rendered hepatocytes sensitive to secondary stress, which subsequently produced apoptosis and hepatocellu lar necrosis. Not all rabbits showed evidence of hepatic toxicity, suggesti ng that individual or species differences in any step along this pathway ma y account for idiosyncratic responses. These differences may be roughly app lied to other metabolic idiosyncratic hepatotoxic responses and include var iations in drug metabolism, effects on mitochondrial function, nutritional status, and health or underlying disease. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.