Oxidation of 1,4-dihydropyridines by prostaglandin synthase and the peroxidic function of cytochrome P-450. Demonstration of a free radical intermediate.

Oxidation of 1,4-dihydropyridines by the hydroperoxidic function of cytochrome P-450 and prostaglandin synthase was investigated using felodipine as a model substance. Nifedipine and the 2,6-dichlorophenyl analogue of felodipine were used in some experiments with similar results. Felodipine was metabolized to a pyridine metabolite in vitro when incubated with liver microsomes and cumene hydroperoxide, as well as with ram seminal vesicle microsomes and arachidonic acid. The oxidation of 1,4-dihydropyridines is proposed to proceed via formation of a free radical intermediate, judging from EPR analysis with the spin trap POBN. When reduced glutathione was added the EPR signal was decreased as well as the formation of the pyridine metabolite while an oxidation of glutathione was observed. This effect was due to a reduction of the radical intermediate back to felodipine by glutathione. Felodipine interacts with the hydroperoxidase activity of prostaglandin synthase, since the pyridine metabolite was formed also when 15-hydroperoxyeicosatetraenoic acid was used as a substitute for arachidonic acid. Indomethacin could only inhibit the metabolism of felodipine when arachidonic acid was used as substrate. The cooxidation of felodipine by prostaglandin synthase is associated with an increased metabolism of arachidonic acid. This was further supported by a stimulated oxygen consumption and an increased formation of prostaglandin E2.