Comparative study of phenothiazine derivatives on monoamine metabolism-- direct correlation between the concentrations of drugs and monoamine metabolites in the brain

S Shibanoki, T Kubo and K Ishikawa

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.

Volume 240, Issue 3, pp. 959-965, 03/01/1987
Copyright © 1987 by American Society for Pharmacology and Experimental Therapeutics