Prolonged toxicity studies with γ-(4-methylpiperidino)- p-fluorobutyrophenone, a new neuroleptic agent

Abstract

The toxicity of γ-(4-methylpiperidino)- p-fluorobutyrophenone (FG5111) was studied during its daily po administration to rats and beagle dogs over a 13-wk period. Preliminary dose ranging experiments showed fatalities and central nervous system intoxication at 200 mg/kg/day in both species. During the main experiment in both species routine studies were made of signs of reaction, body weight, food consumption, blood and urine constituents together with postmortem pathologic and histologic examinations. In rats 120 mg/kg/day produced occasional signs of pharmacologic overdosage and had an inhibitory influence upon growth but was otherwise tolerated without adverse response. A dose of 40 mg/kg/day also inhibited growth, but 10 mg/kg/day did not. For the main experiment in dogs, daily doses of 20 or 100 (reduced after the death of one animal to 80) mg/kg/day were given and produced effects similar to those found in rats; the dog, however, proved to be more susceptible. No other evidence of drug-induced effects were found in either species. FG5111 showed an unusually low level of cumulative toxicity in both species; possibly resulting from a high rate of metabolism and excretion as reported by other workers. No mechanism of action, nor target organ could be demonstrated, although penetration of the central nervous system was obvious from the symptoms, confirming earlier radioactive tracer studies in mice.