Are interspecies comparisons in the toxicity of centrally acting drugs valid without brain concentrations? A commentary.

Many pharmacological and toxicological studies of centrally acting drugs are undertaken in animals at doses expressed in mg.kg-1, and the results extrapolated to the clinical dose in man. Safety margins based on such no or lowest effect levels may have little relevance since they do not take into account differences in the kinetics and metabolism of the compounds. These deviations are accentuated when extremely high doses are used, and saturation of metabolism occurs.