Vol. 283, Issue 3, 1356-1366, 1997

In Vivo Effects of Remoxipride and Aromatic Ring Metabolites in the Rat¹

Sven Ahlenius, Evalena Ericson, Viveka Hillegaart, Lars B. Nilsson, Peter Salmi and Agneta Wijkström

Departments of Behavioral and Biochemical Pharmacology (S.A., E.E., V.H., P.S.) and Bioanalysis (L.B.N., A.W.), Astra Arcus AB, S-151 85 Södertälje, Sweden

The in vivo effects of remoxipride, in relation to some of its identified metabolites, were investigated in adult male Sprague-Dawley rats. The methods used included: (1) estimation of the in vivo rate of brain monoamine synthesis by measuring the accumulation of dihydroxyphenylalanine and 5-hydroxytryptophan after decarboxylase inhibition; (2) observations of spontaneous locomotor activity in a photocell-equipped open-field arena (0.5 m²); (3) treadmill locomotion (4 m min¹); (4) inclined grid (60°) catalepsy test; (5) d-amphetamine-induced (1.0 mg kg¹) hyperlocomotion;(6) quinpirole-induced (0.4 mg kg¹) hypothermia. By use of one or more of these tests, the findings with remoxipride were as follows: First, remoxipride had a late onset of action (up to 3 h). Second, potency and efficacy depended on exposure to hepatic metabolism. Thus, intraperitoneal administration was more effective than the subcutaneous route, whereas virtually all biological effects were lost on intracerebroventricular administration. The ED₅₀ values (µmol kg¹, neostriatal dihydroxyphenylalanine accumulation) for remoxipride and a range of its phenolic aromatic ring metabolites were: remoxipride (20), NCQ-344 (0.01), FLA-797 (0.1), FLA-908 (2.2), NCQ-436 (25) and NCQ-469 (30). Considering remoxipride as a nonclozapine atypical antipsychotic drug, together with the fact that remoxipride behaves as a prodrug in the laboratory studies above, further characterization of the pharmacodynamic profile of its metabolites remains a challenge.