Abstract

The biotransformation of the calcium antagonist felodipine was investigated in liver microsomes from rat, dog, and man. The metabolites were quantified and identified by gradient elution reverse phase liquid chromatography, liquid scintillation analysis, and GC/MS. Ten metabolites were identified, including the pyridine analogue of felodipine, two carboxylic mono acids, two ester lactones, as well as the corresponding open hydroxy acid forms, and a lactonic compound with a carboxylic acid group. The presence of two decarboxylated products was also verified. Metabolites with an intact dihydropyridine nucleus were not detected. The total pool of metabolites formed in vitro was more lipophilic than that excreted in urine from the same species. The metabolic pathways were similar in the three species studied, although quantitative differences were observed. Comparison between incubations with liver microsomes from male and female rats indicated that the females metabolized felodipine more slowly than the males. From a more detailed quantitative analysis of eight metabolites, in relation to incubation time, it was apparent that the hydroxylation of the 2- and 6-methyl groups occurred at a faster rate (0.027 min-1) than did the ester hydrolysis (0.016 min-1). These hydroxy metabolites rearranged spontaneously to lactones. The results from this study indicate that the open hydroxy acid metabolites were formed enzymatically from the corresponding lactones. A metabolic scheme for the overall metabolism of felodipine is given and discussed with reference to the in vivo situation.