Variation in toxicologic response of species to an analgesic

Abstract

Subacute oral administration of an experimental analgesic compound, l-2-(1-methyl-2-piperidyl)-1,1-diphenylethyl propionate hydrochloride, to four species of animals produced a variety of toxicologic responses. Rats tolerated oral doses up to 100 mg/kg/day for periods of 1 or 2 months without adverse clinicopathologic effects. Pregnant rabbits tolerated oral doses up to 80 mg/kg/day for 8 days during the period of embryogenesis without adverse effects upon either the doe or her offspring. In contrast, daily oral doses of 30 mg/kg or more produced emesis, weight loss, depression, unconsciousness, and, occasionally, death in both dogs and monkeys, and higher dosages usually caused death. Liver function was impaired in dogs but not in monkeys, although intracytoplasmic structures compatible with myelin figures occurred in the hepatocytes in both species. In addition, several monkeys had areas of demyelination in the brain which involved the white tracts of the cerebral gyri. These variations in response to a test agent reemphasize species differences and the difficulty in extrapolating toxicity data from one species to another. Because of the complexity of these findings, the compound was withdrawn from consideration as a candidate for clinical trials in man.