RT Journal Article
SR Electronic
T1 Stereoselective metabolism of felodipine in liver microsomes from rat, dog, and human.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 889
OP 894
VO 19
IS 5
A1 Eriksson, U G
A1 Lundahl, J
A1 Bäärnhielm, C
A1 Regårdh, C G
YR 1991
UL http://dmd.aspetjournals.org/content/19/5/889.abstract
AB 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, Vmax or KM. In human liver microsomes, the (R)-enantiomer was metabolized more readily than (S)-felodipine. The mean value of KM was lower for (R)-felodipine, while the Vmax values of the enantiomers were similar. The intrinsic clearance, defined as the ratio of Vmax and KM, 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.