The cataleptic effect of
remoxipride was examined in the horizontal bar test after i.v.,i.p. and s.c. administration to male rats.
Remoxipride induced immediate
catalepsy after high i.v. doses (ED50 = 49 mumol/kg) while peak effects were seen 60-90 min after i.p. administration (ED50 = 38 mumol/kg). Following s.c. administration
remoxipride failed to produce a statistically significant
catalepsy in the 20-100 mumol/kg dose range (ED50 > 100 mumol/kg). In contrast,
haloperidol was found to be more effective in inducing
catalepsy after i.v. (ED50 = 0.4 mumol/kg) than after i.p. or s.c. administration (ED50 = 0.9 mumol/kg). The atypical
antipsychotic profile of
remoxipride was more pronounced when the compound was given i.v. or s.c. as compared with the i.p. route. Plasma and brain (striatum and nucleus accumbens) concentrations of
remoxipride and its active phenolic metabolites
FLA 797(-) and
FLA 908(-) were measured by high performance liquid chromatography. The 40 mumol/kg dose of
remoxipride resulted in plasma and brain concentrations of
remoxipride which were 300-1000-fold higher (depending on the route of administration) than the most potent of the phenolic metabolites, e.g.,
FLA 797(-). The plasma and brain concentrations of
remoxipride and its phenolic metabolites were related to DA D2 receptor blocking potency and to the temporal course and effectiveness to induce
catalepsy. This analysis suggested that the unbound concentrations of the phenolic metabolites were too low to play a major role in the DA blocking action of
remoxipride. However,
FLA 797(-) may contribute marginally to the cataleptic effects following high (i.p.) doses of
remoxipride.