STEREOSELECTIVE METABOLISM OF FELODIPINE IN LIVER-MICROSOMES FROM RAT, DOG, AND HUMAN

Felodipine, a 1,4-dihydropyridine derivative, is a potent, vasoselective calcium antagonist that is used clinically as a racemic mixture of two stereoisomers. In the rat, dog, and human, the bioavailability of an oral dose is about 15% because of high first-pass metabolism. Oxidation of the dihydropyridine ring to the corresponding achiral, pharmacologically inactive pyridine metabolite is the predominant metabolic step. In the liver, this metabolism is catalyzed by cytochrome P-450. In the present study, the metabolism of (R)- and (S)-felodipine was compared in vitro in liver microsomes from rats, dogs, and humans. Slightly higher rates of metabolism were found for the (S)-enantiomer in rat and dog liver microsomes. However, no significant differences were observed in the Michaelis-Menten parameters, V(max) or K(M). In human liver microsomes, the (R)-enantiomer was metabolized more readily than (S)-felodipine. The mean value of K(M) was lower for (R)-felodipine, while the V(max) values of the enantiomers were similar. The intrinsic clearance, defined as the ratio of V(max) and K(M), was about two times higher for (R)-felodipine. Assuming complete absorption and that the bioavailability is determined by the first-pass metabolism in the liver, these in vitro results suggest that the bioavailability of (S)-felodipine in vivo is about two times higher than that of (R)-felodipine.