SMON and Pharmacokinetics of Chinoform with Special Reference to Animal Species Difference

Abstract

The experimental reproduction of SMON using several kinds of animals given a prolonged administration of chinoform has been carried out by many investigators because of the importance to solve the problem of etiology in the SMON. In these experiments, it is demonstrated that a marked species difference was observed in the relationship between the doses given to animals and the frequency of the onset of neurologic symptoms. Although dogs were accepted as the most suitable animal model for SMON, pathological changes in the peripheral nerve of the dog were not observed. The blood level or tissue distribution of chinoform after oral, intravenous or intraperitoneal administration of the drug differed in the animal species. Thus, it is considered that the species difference in the onset of neurologic symptoms is principally caused by the difference in pharmacokinetics of chinoform in each animal. Moreover, for the onset of neurologic symptoms in animals, perhaps it is necessary to maintain the level of unconjugated chinoform in the nerve tissues around several to over ten μg/ml for three or four weeks as well as that in SMON patients while the neurologic symptoms or pathological changes do not appear in some kinds of animals at these levels. In a study on the cellular toxicity of chinoform, many other problems remain to be solved although degeneration or uncoupling on oxidative phosphorylation in mitochondria of the axons by chinoform and lipid peroxidation of the membrane by chinoform-ferric chelate have been already shown.