Eriksson U G, Lundahl J, Bäärnhielm C, Regårdh C G
Hässle Research Laboratories, Mölndal, Sweden.
Drug Metab Dispos. 1991 Sep-Oct;19(5):889-94.
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.
非洛地平是一种1,4 - 二氢吡啶衍生物，是一种强效的、血管选择性钙拮抗剂，临床上使用的是两种立体异构体的外消旋混合物。在大鼠、狗和人类中，由于首过代谢率高，口服剂量的生物利用度约为15%。二氢吡啶环氧化为相应的无手性、药理活性的吡啶代谢物是主要的代谢步骤。在肝脏中，这种代谢由细胞色素P - 450催化。在本研究中，对大鼠、狗和人类肝脏微粒体中（R）-和（S）-非洛地平的代谢进行了体外比较。在大鼠和狗的肝脏微粒体中，（S）-对映体的代谢率略高。然而，在米氏参数Vmax或KM中未观察到显著差异。在人类肝脏微粒体中，（R）-对映体比（S）-非洛地平更容易代谢。（R）-非洛地平的KM平均值较低，而对映体的Vmax值相似。定义为Vmax与KM之比的内在清除率，（R）-非洛地平约高两倍。假设完全吸收且生物利用度由肝脏中的首过代谢决定，这些体外结果表明（S）-非洛地平在体内的生物利用度约为（R）-非洛地平的两倍。
