Cytochrome P-450-dependent oxidation of felodipine—a 1,4-dihydropyridine—to the corresponding pyridine

Abstract

1. Felodipine, a 1,4-dihydropyridine diester, is metabolized to its corresponding pyridine analogue by rat-liver microsomes.

2. Kinetic studies showed similar K_m, V_max and t_1/2 for the formation of the pyridine metabolite and the disappearance of felodipine, indicating that oxidation of felodipine to the corresponding pyridine analogue is the major pathway of metabolism.

3. Response to inhibitors such as CO, SKF 525-A and metyrapone indicates participation of cytochrome P-450 in the aromatization of felodipine. Phenobarbital pretreatment markedly increased the metabolism of felodipine and its pyridine analogue.

4. Felodipine pretreatment had no effect on the cytochrome P-450 concn. in rat-liver microsomes, nor on the rate of its own metabolism, but a slight increase was observed in the rate of metabolism of four standard substrates.