Disruption of mitochondrial activities in rabbit and human hepatocytes by a quinoxalinone anxiolytic and its carboxylic acid metabolite

The quinoxalinone anxiolytic, panadiplon, was dropped from clinical develop ment due to unexpected hepatic toxicity in human volunteers. Subsequent exp erimental studies in rabbits demonstrated a hepatic toxicity that resembled Reye's syndrome. In the present studies, we examined the effects of panadi plon and a metabolite, cyclopropane carboxylic acid (CPCA) on hepatic mitoc hondrial activities in vitro and ex vivo. Acute inhibition of beta-oxidatio n of [C-14]palmitate was observed in rabbit and human hepatocyte suspension s incubated with 100 mu M panadiplon. Panadiplon (30 mu M) also reduced mit ochondrial uptake of rhodamine 123 (R123) in cultured rabbit and human, but not rat hepatocytes, following 18 h exposure. CPCA also impaired beta-oxid ation and R123 uptake in rabbit and human hepatocytes. R123 uptake and beta -oxidation in cells from some donors was not impaired by either agent, and cell death was not observed in any experiment. Hepatocytes isolated from pa nadiplon-treated rabbits had reduced palmitate beta-oxidation rates and inh ibited mitochondrial R123 uptake; R123 uptake remained inhibited until 48-7 2 h in culture. Rabbit mitochondrial respiration experiments revealed a sli ghtly lower ratio of ATP formed/oxygen consumed in panadiplon-treated anima ls; direct exposure of normal rabbit liver mitochondria to panadiplon did n ot have this effect. Hepatocytes isolated from panadiplon-treated rabbits s howed reduced respiratory control ratios and lower oxygen consumption compa red to controls. Our results indicate that panadiplon induces a mitochondri al dysfunction in the liver, and suggest that this dysfunction may be attri buted to the carboxylic acid metabolite. (C) 1998 Published by Elsevier Sci ence Ireland Ltd. All rights reserved.