RT Journal Article
SR Electronic
T1 Characteristics of warfarin hydroxylation catalyzed by human liver microsomes.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 265
OP 270
VO 17
IS 3
A1 A E Rettie
A1 A C Eddy
A1 L D Heimark
A1 M Gibaldi
A1 W F Trager
YR 1989
UL http://dmd.aspetjournals.org/content/17/3/265.abstract
AB The oxidative biotransformation of (R)- and (S)-warfarin was studied in human liver microsomes to determine whether an in vitro model could be established that would correspond to the in vivo profile that is generally observed. The quantitative pattern of oxidized products obtained from warfarin in vitro changed dramatically as a function of substrate concentration. Apparent Km values for the formation of 4', 6, 7, and 8-hydroxywarfarin indicated the presence of two easily distinguishable subsets of human liver cytochrome P-450; a high affinity subset (Km 3-15 microM) and a low affinity subset of isozymes (Km greater than 200 microM). The high affinity subset is primarily responsible for the metabolic profile of the biologically more potent (S)-enantiomer in vivo, whereas the low affinity subset is largely responsible for metabolism of the (R)-enantiomer. Apparent Vmax values alone did not reflect the relative in vivo formation clearances of the phenolic metabolites from either antipode, because the low affinity-high capacity component masked the metabolic profile of the (S)-enantiomer. However, the rank order of intrinsic clearance, Vmax/Km, for each metabolite was in good agreement with regio- and stereoselective metabolism in vivo. This investigation highlights the need for rigorous kinetic characterization of an in vitro model before reasonable correlation can be expected with in vivo data.