Oxidation of nilvadipine, a new dihydropyridine calcium antagonist, to the corresponding pyridine by rat liver microsomes.

1. The oxidation of nilvadipine, a 1,4-dihydropyridine derivative, by rat liver microsomes and sex-related differences in this activity were investigated. 2. The kinetic data (Km and Vmax) for the formation of the corresponding pyridine analogue by liver microsomes from adult male rat (7 weeks old) were similar to those for the disappearance of nilvadipine, indicating that the aromatization of nilvadipine is the primary metabolic step. 3. The formation of the pyridine analogue required the presence of NADPH-generating system and was significantly inhibited by cytochrome c, metyrapone, and 7,8-benzoflavone, indicating the participation of cytochrome P-450. Phenobarbital pretreatment of rats caused an increase in the metabolism of nilvadipine. 4. Nilvadipine oxidase activity in adult male rat was about 10 times higher than that in adult female rat. In contrast, marked sex-related differences were not seen in immature rat (21 days old), and the activity was approximately twice as high as that in adult female rat. No activity was detected in the postmitochondrial fractions of lung, kidney, brain, heart, pancreas or small intestine of adult male rat.