The stereoselective oxidation of nilvadipine (NV), a new 1,4-dihydropyridine calcium antagonist, to the corresponding pyridine analog was studied after incubation of (+)- and (-)-NV with rat and dog liver microsomes. The rates of formation of the pyridine analog and disappearance of NV were similar for each species, indicating that aromatization of NV is the primary metabolic step. Formation of the corresponding pyridine required the presence of an NADPH-generating system and was significantly inhibited by carbon monoxide and metyrapone, indicating the participation of cytochrome P-450. In male rat liver microsomes, the apparent Km values for the formation of the pyridine from (+)- and (-)-NV were 11.2 and 8.1 microM, and the Vmax values were 7.48 and 3.37 nmol/mg of protein/min, respectively. Therefore, the Vmax/Km value, which is equivalent to the intrinsic clearance of the drug, for the oxidation of (+)-NV was 1.59-fold greater than that for the oxidation of the (-)-enantiomer. In female rats, (-)-NV oxidation exhibited two distinct apparent Km values, whereas the that of the (+)-enantiomer did not. The (+)/(-) ratio of Vmax/Km was 1.23. On the other hand, in male dog microsomes the Km values for (+)- and (-)-NV were 21.9 and 12.2 microM, and Vmax values were 3.02 and 2.45 nmol/mg of protein/min, respectively; the (+)/(-) ratio of Vmax/Km was 0.69. These results indicate that the stereo-selective oxidation of NV is species dependent and is sex related in rat liver.