title: Comparative study of phenothiazine derivatives on monoamine metabolism--direct correlation between the concentrations of drugs and monoamine metabolites in the brain.
abstract: The pharmacokinetics (distribution and elimination) and pharmacodynamics (biochemical effects on monoamine systems) of phenothiazines including the novel compound, E-0663 (10-[3-(3-hydroxypyrrolidinyl)-propyl]-2-trifluoromethyl phenothiazine), in the central nervous system were investigated concurrently in mice using high-performance liquid chromatography with electrochemical detection. The elimination rate of E-0663 from the brain was longer than that of the classical compounds, chlorpromazine, perphenazine and triflupromazine. The phenothiazine (0.01-100 mumol/kg i.v.) increased the metabolites of catecholamines. Direct correlation analysis was applied to the intracerebral concentrations of the drugs and monoamine-related substances. Significant correlations were observed between the concentrations of drugs and dopamine metabolites (3,4-dihydroxyphenylacetic acid and homovanillic acid). The relative potency of the drugs for the effect on the extraneuronal process was promethazine less than chlorpromazine less than E-0663 less than triflupromazine less than perphenazine by covariance analysis. On the other hand, noradrenaline metabolite (3-methoxy-4-hydroxyphenylethylene glycol) also revealed a significant correlation, and the potency was highest in the case of E-0663. These results suggest that E-0663 possessed different pharmacokinetic profiles and a different spectrum in its action on monoamine metabolism from classical phenothiazines. The method described here is simple for comparing the real potency and is useful as a new approach in the biochemical pharmacology of centrally acting drugs.
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D001679:Biogenic Amines / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D006207:Half-Life; D007700:Kinetics; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010640:Phenothiazines; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D014150:Antipsychotic Agents; D001679:Biogenic Amines; D010640:Phenothiazines