The Distribution Pattern of a Series of Tricyclic and Bicyclic Thymoleptics Compared with their Lipophilic Properties and Binding to Plasma Proteins

Eight thymoleptic drugs were labelled with carbon‐14. Four of the drugs were of the tricyclic type (amitriptyline/nortriptyline and melitraced litracen), the others belonged to the bicyclic phthalane and thiophthalane structures. The drugs were given intravenously to male albino rats in doses of 5 mg/kg. At fixed times after injection the animals were killed by exsanguination. Blood was collected and examined together with different organs for contents of radioactivity. Chromatographic estimations were made on extracts of the brain. The relative lipophilic properties of the drugs were determined as well as the binding to plasma proteins. The concentration of radioactivity in the lungs was in all cases higher after a secondary than after the corresponding tertiary amitte. In the brain the initial concentrations were highest after the tertiary amines, but at later periods the concentrations were almost the same after a tertiary and the corresponding secondary amine. Among the tertiary and the secondary amines, respectively, the drugs of the tricyclic type showed the highest brain concentrations. The chromatographic estimations of brain extracts showed that after the administration of a tertiary amine, the parent drug accounted for almost all radioactivity, while after a secondary amine the N‐demethylation product was present in considerable amounts. The lipophility studies showed that the tertiary amines were in all caws much more lipophilic than their corresponding secondary amines. The data for the binding to plasma proteins did not show any general trend. It is concluded that the penetration of drugs into the brain is only partly explained by the lipophility of the drugs. The binding to plasma proteins does not seem to influence the distribution. Particular attention is drawn to the astonishing finding, that more N‐demethylated metabolites are found after secondary amines than after tertiary amines, though the latter are N‐demethylated at a higher rate.