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Phenothiazine derivatives and intracerebral monoamine metabolism: Application of direct correlation analysis between the levels of drugs and monoamine metabolites in rat brain



Phenothiazine derivatives and intracerebral monoamine metabolism: Application of direct correlation analysis between the levels of drugs and monoamine metabolites in rat brain



Nichidai Igaku Zasshi 53(9): 701-709



Direct correlation analyses between the distribution of phenothiazines (pharmacokinetics) and the biochemical effects of the drugs on monoamine metabolism (pharmacodynamics) were undertaken to characterize the effects of phenothiazines including chlorpromazine (CPZ) and the novel compound, E-0663 (10-(3-(3-hydroxypyrrolidinyl)-propyl)-2-trifluoromethyl phenothiazine), on the monoaminergic system in the rat striatum and hypothalamus. The concentrations of phenothiazines and monoamine related substances were determined concurrently in the same sample by high performance-liquid chromatography with electrochemical detection. The concentration of CPZ was significantly correlated with the concentrations of DOPAC and HVA in the striatum and hypothalamus, while no significant correlations were observed between the drug and 5-HIAA concentrations in both regions. A significant correlation was noted between the concentrations of CPZ and MOPEG in the hypothalamus but not in the striatum. On the other hand, similar results to the corrrelations of the CPZ and monoamine metabolites concentrations were obtained in the case of E-0663, and E-0663 was more potent in some cases. These results suggest that the dopaminergic system is primarily involved in the mechanism underlying the pharmacological effects of phenothiazines, and the analysis employed in the present study is useful as a new approach to the biochemical pharmacology of phenothiazines.

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