INDUCTION OF A HEPATIC TOXIC SYNDROME IN THE DUTCH-BELTED RABBIT BY AQUINOXALINONE ANXIOLYTIC

The non-benzodiazepine anxiolytic, panadiplon, was discontinued from c linical development due to evidence of hepatic toxicity in human volun teers that was not predicted by rat or monkey preclinical development studies. The present study was conducted to examine potential toxicity in the rabbit. Three groups of female rabbits were administered vehic le, 10 mg/kg per day or 20 mg/kg per day of panadiplon by oral gavage for 14 days. Animals in the 20 mg/kg group lost weight, and 6/10 devel oped a profound lethargy. Hepatic toxicity was observed in treated ani mals, evidenced by dose- and time-related increases in serum transamin ase activities, gross hepatic lesions and multifocal centrilobular nec rosis. Hepatic microvesicular steatosis was evident in treated animals ; lipid analysis revealed a 123% increase in hepatic triglyceride. A t ime-dependent increase in serum triglyceride levels was observed in th e high-dose group beginning on day 4. Hepatic glycogen was reduced, an d histochemical examination revealed the reduction to be heterogeneous across the lobule with some areas showing a complete absence of glyco gen. One rabbit in each drug-treated group showed mild hypoglycemia at day 12, and 4/10 rabbits in the high-dose group showed hyperglycemia at days 12-14. We conclude that panadiplon produced a microvesicular s teatosis and hepatic toxicity in the rabbit. The observed toxicity res embled a Reye's syndrome-like toxicity produced by a variety of mitoch ondrial fatty acid oxidation inhibitors.