Induction of a hepatic toxic syndrome in the Dutch-belted rabbit by a quinoxalinone anxiolytic.
The non-benzodiazepine anxiolytic, panadiplon, was discontinued from clinical development due to evidence of hepatic toxicity in human volunteers 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 vehicle, 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 developed a profound lethargy. Hepatic toxicity was observed in treated animals, evidenced by dose- and time-related increases in serum transaminase activities, gross hepatic lesions and multifocal centrilobular necrosis. Hepatic microvesicular steatosis was evident in treated animals; lipid analysis revealed a 123% increase in hepatic triglyceride. A time-dependent increase in serum triglyceride levels was observed in the high-dose group beginning on day 4. Hepatic glycogen was reduced, and histochemical examination revealed the reduction to be heterogeneous across the lobule with some areas showing a complete absence of glycogen. 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 steatosis and hepatic toxicity in the rabbit. The observed toxicity resembled a Reye's syndrome-like toxicity produced by a variety of mitochondrial fatty acid oxidation inhibitors.
Ulrich
R G
RG
Investigative Toxicology Unit, Upjohn Laboratories, Kalamazoo, MI 49001, USA.
Bacon
J A
JA
Branstetter
D G
DG
Cramer
C T
CT
Funk
G M
GM
Hunt
C E
CE
Petrella
D K
DK
Sun
E L
EL
D000818:Animals; D014151:Anti-Anxiety Agents / Q000633:toxicity*; D004247:DNA / Q000378:metabolism; D005234:Fatty Liver / Q000097:blood / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D005260:Female; D008112:Liver Glycogen / Q000378:metabolism; D010069:Oxadiazoles / Q000633:toxicity*; D011506:Proteins / Q000378:metabolism; D011810:Quinoxalines / Q000633:toxicity*; D011817:Rabbits; D013223:Statistics as Topic
D014151:Anti-Anxiety Agents; D008112:Liver Glycogen; D010069:Oxadiazoles; D011506:Proteins; D011810:Quinoxalines; D004247:DNA; C069443:panadiplon