Predicting toxicokinetic parameters in humans from toxicokinetic data acquired from three small mammalian species

Abstract

Values for the indepedent kinetic variables, clearance (CL) and volume of distribution (V), for six xenobioticsantipyrine, ethosuximide, phencyclidine, theophylline, valproic acid and warfarin—were culled from the literature for each of three small subhuman species and for humans, and then allometrically scaled. Scaling was performed in two ways. First, using kinetic data acquired for three small subhuman species and for man, scaled parameters were observed for goodness of fit to a standard allometrie expression. Second, scaled parameters were averaged for three subhuman species. Mean scaled kinetic parameters from only three species were used to predict half-life values of the xenobiotics in humans. Finally, predicted percentages of the xenobiotic burdens remainig in humans at the end of four allometrically-predicted half-lives were compared with the expected percentages of remainig xenobiotic based upon four actual half-lives in humans. The results suggest that it may be feasible to estimate, using three small subhuman specie, allometrically-derived toxicokinetic parameters of some substances in man with sufficient accuracy to be of practical value.