Abstract
The scientific literature indicates that the biotransformation of xenobiotics in man is more similar to that observed in the non-human primate than to other laboratory animal species. The main objective of the current investigation was to compare the ability of 3 species of non-human primate, the rhesus monkey (Macaca mulatta), the cynomolgus monkey (Macaca fascicularis) and the baboon (Papio species), to conjugate xenobiotics with glutathione since such information is lacking in the literature. The metabolism and pharmacokinetics of ethacrynic acid, a diuretic known to be extensively metabolised by glutathione conjugation in several other animal species, was studied in the non-human primates. The results indicate that the overall capacity for glutathione conjugation in the non-human primate is large, and demonstrate that various organs and tissues can simultaneously contribute to the detoxication and elimination of various xenobiotics by this pathway. In common with other laboratory animal species, the non-human primate excreted the major proportion of radioactivity, following administration of [14]C-ethacrynic acid, in the bile. The radioactivity in the bile was mainly associated with metabolites which had resulted from the initial conjugation of ethacrynic acid with glutathione, and the subsequent metabolism of this conjugate via the mercapturic acid pathway. There were notable species differences, between the non-human primates and other laboratory animals, in the proportions of the various metabolites which were excreted in the bile. Although the concentrations of glutathione in the various tissues of the non-human primate were similar to those reported for other mammals, species differences occurred in the rates of glutathione conjugation and the subsequent metabolism of the glutathione conjugate. A significant finding concerned the extent to which various aB-unsaturated xenobiotics were conjugated with glutathione. There were marked species differences between the non-human primate and the rat in this respect. The rhesus monkey, cynomolgus monkey and the baboon are similar as regards ethacrynic acid metabolism, tissue glutathione concentrations, tissue glutathione S-transferase activities, and the specific activities of the glutathione S-transferase isoenzymes. The rhesus monkey more closely resembles man in these respects, but both other species of non-human primate would appear to be suitable for use in metabolism and toxicological studies of compounds likely to be conjugated with glutathione.