In Vivo Pharmacokinetics of Felodipine Predicted from in Vitro Studies in Rat, Dog and Man

Abstract

Ah.riruc/;The elimination of felodipinc in liver microsomes from dog and man were characterized by K,,, and V,,,.,,. The results were compared with previous data reported lor rat. In all species studied, felodipine was primarily metabolized l o its corresponding pyridine analogue. The elimination rate order was rat > dog > man. The same species difference was observed in vivo for the oral plasma clearance which was; rat 26 l/hr/kg. dog 7.5 Ihr/kg and man 4.3 I/hr/kg. The intrinsic hepatic clearance of felodipine was predicted in viiro from V,,,, over K,,,. The in r>i/ro values were not significantly different from those observed in vivo. Felodipine is a high-clearance drug and the in vivo extraction ratios were about the same in all species: rat 0.80, dog 0.83 and man 0.84. The extraction ratios predicted from the in viiro studies, rat 0.91, dog 0.70 and man 0.80, agreed well with those observed in i~iw.

Scaling Factors for the Extrapolation of In Vivo Metabolic Drug Clearance From In Vitro Data: Reaching a Consensus on Values of Human Micro-somal Protein and Hepatocellularity Per Gram of Liver

“…Cross and Bayliss [50] have commented on hepatocellularity values, emphasising the uncertainty of extrapolating between species and the need for the scaling factors to be clarified. However, despite the current availability of experimentally-determined values of human MPPGL and HPGL [14,21,29,30,42], investigators continue to use earlier estimates based largely on rat data (Fig. 2E).…”

“…Baarnhielm et al, [14] estimated human MPPGL (mean 77 mg.g -1 ) using tissue from the livers of 4 kidney transplant donors following circulatory arrest (1 male, 3 female; age unspecified; CYP used to correct for losses).…”

“…Studies were only included in the meta-analysis if information on both study mean and variability were available, and values were determined using matched homogenate and microsomal samples from the same individual with correction for loss by spectral methods. Thus, with respect to MPPGL, data from five studies [14,30,34,36,53] were excluded since they did not provide values for individual livers, either reporting an overall mean value or generating values of MPPGL from unmatched homogenate and microsomal samples. An overall weighted mean value (WX) of MPPGL of 34 mg.g -1 was calculated from the 108 observations included in the meta-analysis using the following equation: where CV is the coefficient of variation (%).…”

Determinants of Cytochrome P450 2C8 Substrate Binding

“…The dichlorophenyl ring is positioned appropriately in 2C8 for potential oxidation with carbon 4 residing 4.6 Å from the heme iron, but we are not aware of evidence for the oxidation of the compound by P450 2C8. Felodipine is largely converted to the pyridine analog by oxidative dehydrogenation of the dihydropyridine ring, which is predominantly catalyzed by P450 3A4 (34,35). In contrast, troglitazone is not positioned for oxidation, but is known to be oxidized by P450 2C8 (24).…”

Stereoselectivity in drug metabolism

“…Consistent with the in vitro observation, oral bioavailability and AUC of (S)-felodipine was twice as high as that for its antipode in humans. In rats and dogs, less pronounced and opposite oral bioavailability was observed, and the (R)-enantiomer had 40% higher AUC than its antipode [74][75][76]. Likewise, stereoselective pharmacokinetics and in vitro metabolism are also reported for nilvadipine.…”