The fate of p-bromo-methylamphetamine (V-111) in the body

The fate of p-bromo-methylamphetamine (V-111) in the body was studied by means of its radioactive labelled forms in mouse and rat experiments. It was found with the whole body autoradiographic method and liquid-scintillation measurements that the compound is rapidly absorbed by whatever routes of administration and it is rapidly taken up by the tissues from the blood stream. In the central nervous system, it reaches higher concentration than methyl-amphetamine and it leaves the central nervous system more slowly. We have shown with differential centrifugation that V-111 is bound much more avidly to the mitochondrial and microsomal fractions of rat brain than methyl-amphetamine and o-bromo-methyl-amphetamine (V-104). The intensity of binding is proportional to the lipid solubility of the compounds. V-111 and its metabolites are excreted mainly in the urine, and they can be found in small amounts also in the stool. In the case of V-111-3-14C a small amount of 14CO2 appeared in the expired air, too, which is a consequence of the disintegration of the molecule. It has been shown by the radiochromatographic and gas chromatographic, mass-spectrometric analysis of the metabolites that V-111 is excreted partly in unchanged form, nevertheless, the N-demethylated and subsequent products, viz. p-bromo-phenyl-acetone, p-bromo-phenylpropanol, p-bromo-benzoic acid and p-bromo-hyppuric acid are also excreted in the urine. The main metabolic pathway of amphetamine and of its methyl-derivative in rat is p-hydroxylation, which does not take place in the case of p-halogenated V-111. Thus the secondary metabolic pathway (demethylation, oxidative desamination) becomes the main metabolic route of V-111 in this species. The vigorous demethylation of V-111 was proved both in vivo and in vitro. In the rat, demethylating activity increases during prolonged treatment. The latter fact has to be taken into consideration when interpreting the pharmacological tolerance that develops during chronic administration of the compound.