CONCENTRATIONS OF REMOXIPRIDE AND ITS PHENOLIC METABOLITES IN RAT-BRAIN AND PLASMA - RELATIONSHIP TO EXTRAPYRAMIDAL SIDE-EFFECTS AND ATYPICAL ANTIPSYCHOTIC PROFILE

The cataleptic effect of remoxipride was examined in the horizontal ba r test after i.v.,i.p. and s.c. administration to male rats. Remoxipri de induced immediate catalepsy after high i.v. doses (ED(50) = 49 mu m ol/kg) while peak effects were seen 60-90 min after i.p. administratio n (ED(50) = 38 mu mol/kg). Following s.c. administration remoxipride f ailed to produce a statistically significant catalepsy in the 20-100 m u mol/kg dose range (ED(50) > 100 mu mol/kg). In contrast, haloperidol was found to be more effective in inducing catalepsy after i.v. (ED(5 0) = 0.4 mu mol/kg) than after i.p. or s.c. administration (ED(50) = 0 .9 mu mol/ kg). The atypical antipsychotic profile of remoxipride was more pronounced when the compound was given i.v. or s.c. as compared w ith the i.p. route. Plasma and brain (striatum and nucleus accumbens) concentrations of remoxipride and its active phenolic metabolites FLA7 97(-) and FLA908(-) were measured by high performance liquid chromatog raphy. The 40 mu mol/kg dose of remoxipride resulted in plasma and bra in concentrations of remoxipride which were 300-1000-fold higher (depe nding on the route of administration) than the most potent of the phen olic metabolites, e.g., FLA797(-). The plasma and brain concentrations of remoxipride and its phenolic metabolites were related to DA D-2 re ceptor blocking potency and to the temporal course and effectiveness t o induce catalepsy. This analysis suggested that the unbound concentra tions of the phenolic metabolites were too low to play a major role in the DA blocking action of remoxipride. However, FLA797(-) may contrib ute marginally to the cataleptic effects following high (i.p.) doses o f remoxipride.