title: Concentrations of remoxipride and its phenolic metabolites in rat brain and plasma. Relationship to extrapyramidal side effects and atypical antipsychotic profile.
abstract: 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.
authors.affiliation: Astra Arcus AB, CNS Preclinical R & D, Södertälje, Sweden.
authors.forename: S O
authors.initials: SO
authors.lastname: Ogren
authors.forename: J
authors.initials: J
authors.lastname: Lundström
authors.forename: L B
authors.initials: LB
authors.lastname: Nilsson
mesh_terms: D000818:Animals; D001480:Basal Ganglia Diseases / Q000139:chemically induced* / Q000503:physiopathology; D001921:Brain / Q000378:metabolism*; D002375:Catalepsy / Q000139:chemically induced; D002851:Chromatography, High Pressure Liquid; D002940:Circadian Rhythm; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017330:Remoxipride / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012457:Salicylamides / Q000493:pharmacokinetics; D013056:Spectrophotometry, Ultraviolet
chemical_list: D012457:Salicylamides; D017330:Remoxipride; C084324:FLA 908; C050313:FLA 797; D006220:Haloperidol