Metabolism of sertindole: identification of the metabolites in the rat and dog, and species comparison of liver microsomal metabolism

Abstract

1. The main exretion pathways of a novel antipsychotic drug, sertindole, in the rat and dog are faecal excretion via intestinal secretion and biliary excretion respectively.

2. Similar liver microsomal metabolic patterns were observed in the rat, monkey, and man, and Lu 30–131 (5-hydroxy-serindole) and Lu 30–148 (4-hydroxy-serindole) were the major metabolites, and Lu 25–073 (nor-sertindole) and Lu 28–092 (dehydro-sertindole) were minor ones. In the dog, however, Lu 31–096 (3′-fluoro-4′-hydroxy-sertindole) and Lu 30–148 (4-hydroxy-sertindole) were the major metabolites, and Lu 25–073 (nor-sertindole), Lu 28–092 (dehydro-sertindole), and Lu 30–131 (5-hydroxy-sertindole) were minor ones. These findings suggest that the metabolism of sertindole in man resembles those in the rat and monkey and is different from that in the dog.

3. Rat in vitro and in vivo liver metabolites, dog liver microsomal metabolites, and dog biliary metabolites were isolated and identified by liquid chromatography/mass spectrometry and/or ¹H-nmr.

4. Two metabolites, Lu 31–096 (3′-fluoro-4′-hydroxy-sertindole) and Lu 31–154 (3′-fluoro-4′-hydroxy-dehydro-sertindole), were formed via the ‘NIH shift’ mechanism.

5. Sertindole is metabolized by hydroxylation at the 4- and 5-positions on the imidazolidinone ring, N-dealkylation, and an NIH shift at the fluorophenyl group. Further metabolism (dehydration, oxidation, hydroxylation, glucuronidation and sulphation) was also observed.

6. In the rat, oxidation at the imidazolidinone ring and N-dealkylation are the main metabolic reactions. On the other hand, in the dog, the NIH shift at the fluorophenyl group, followed by conjugation is the main metabolic pathway.