CONCENTRATIONS OF REMOXIPRIDE AND ITS PHENOLIC METABOLITES IN RAT-BRAIN AND PLASMA - RELATIONSHIP TO EXTRAPYRAMIDAL SIDE-EFFECTS AND ATYPICAL ANTIPSYCHOTIC PROFILE
So. Ogren et al., CONCENTRATIONS OF REMOXIPRIDE AND ITS PHENOLIC METABOLITES IN RAT-BRAIN AND PLASMA - RELATIONSHIP TO EXTRAPYRAMIDAL SIDE-EFFECTS AND ATYPICAL ANTIPSYCHOTIC PROFILE, Journal of neural transmission, 94(3), 1993, pp. 199-216
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.