Disposition of remoxipride in different species. Species differences in metabolism

Widman, M.; Nilsson, L.B.; Bryske, B.; Lundström, J.

Arzneimittel-Forschung 43(3): 287-297


ISSN/ISBN: 0004-4172
PMID: 8489555
Document Number: 422179
The pharmacokinetics and metabolism of the new antipsychotic agent remoxipride ((S)-(-)-3-bromo-N-((1-ethyl-2-pyrrolidinyl)methyl)-2,6-dimethoxybenzamide, FLA731(-), Roxiam, CAS 80125-14-0) was studied in rodents (mice, rats, hamsters), dogs and human subjects using the unlabelled or the labelled (3H or 14C) drug. Oral administration of 20-40 mu-mol/kg to animals and apprx 3 mu-mol/kg to human volunteers showed that the absorption of remoxipride through the intestinal wall was rapid and almost complete in all species. However, the bioavailability was low in the rodents ( lt 10% in mice and hamsters and lt 1% in rats) due to an extensive first-pass elimination in the hepato-portal system. Blood clearance estimated after the same intravenous doses was high in rodents and similar to or exceeding normal liver blood flow. In dogs and humans, clearance values were low and the bioavailability high ( gt 90%). In mice and rats the contribution of renal clearance to the total clearance was approximately 10%, while it was higher in dogs ( apprx 15%) and humans ( apprx 30%). Species differencies were also observed in the degree of protein binding which was low in rodent plasma (20-30%) but fairly high in canine and human plasma ( apprx 80%). In dogs and humans, remoxipride was shown to bind primarily to the plasma a-1-acid glycoprotein fraction. In accordance with the binding data, the volume of distribution (V-ss) was higher in rodents (3-6 l/kg) than in dogs (1.6 l/kg) and man (0.7 l/kg). Studies in dogs with 14C-remoxipride showed that the compound was rapidly distributed to tissues and eliminated at rates similar to that in plasma (t-1/2 3-4 h). Retention of radioactivity was only observed in melanin-rich tissues. However, studies in pigmented mice showed that the affinity of remoxipride to melanin was lower than that of the other neuroleptics haloperidol and chlorpromazine. The excretion of radioactivity following oral administration of the labelled drug mainly occurred in the urine in all species. However, species differencies were observed in the identification and analysis of the various metabolites present in plasma and excreted in urine. In rodents, metabolic reactions occurred mainly at the aromatic moiety, i.e. O-demethylation and aromatic hydroxylation. The resulting phenols were excreted mainly in conjugated forms. In dogs and humans, the predominant metabolic reactions were oxidations at the alpha-carbons of the pyrrolidine moiety leading to N-demethylated and/or pyrrolidone and hydroxypyrrolidone products. Only the phenolic metabolites have been found to possess pharmacological activity similar to that of remoxipride.

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