Simultaneous Determination of the Pharmacokinetics and Pharmacodynamics of Chlorpromazine in the Brain of Mice

Abstract

The direct correlation analyses between the distribution of chlorpromazine (pharmacokinetics) and the biochemical effects of the drug on monoamine metabolisms (pharmacodynamics) are reported. Both samples for quantitative determination of CPZ and of monoamine transmitters and metabolites were obtained by organic extraction procedures from the same sample. The determinations were carried out by high performance liquid chromatography with electrochemical detection. CPZ affected the concentrations of metabolites of noradrenaline, dopamine and 5-hydroxytryptamine, but not those of the monoamine transmitters themselves. However, simultaneous assay demonstrated differences in effects of the drug on the transmitter systems. The concentrations of HVA and DOPAC were increased over a wide range of intracerebral concentrations of the drug, but those of MOPEG, in the range of higher concentrations. On the other hand, CPZ did not reveal any correlations between the intracerebral concentrations of the drug and 5-HIAA. These results suggest that CPZ affected primarily the dopaminergic system rather than the serotonergic one in the early stage of its biochemical actions. The proposed procedure is demonstrated to be simple and useful as a new approach in biochemical pharmacology. The same procedure can be applicable for other centrally acting drugs.