Metabolic enantiomeric interactions: the inhibition of human (S)-warfarin-7-hydroxylase by (R)-warfarin.
Inhibition of the metabolism of (S)-warfarin, the more pharmacologically active enantiomer of the racemic drug, by (R)-warfarin was investigated in microsomes obtained from three human livers. In each case the production of both (S)-6- and (S)-7-hydroxywarfarin was found to be competitively inhibited by (R)-warfarin. The KiS for inhibition of (S)-6- and (S)-7-hydroxylation by (R)-warfarin ranged from 7.0 to 8.4 microM and from 6.0 to 6.9 microM, respectively, while the KmS for the 6- and 7-hydroxylation of (S)-warfarin ranged from 3.6 to 3.8 microM and from 3.3 to 3.9 microM, respectively. In contrast, except for the 4'-hydroxylation pathway (S)-warfarin was found to be a weak inhibitor of the metabolism of (R)-warfarin. Possible implications of these findings include the following: (1) the kinetic parameters defining the interactions of two enantiomers of a racemic drug with the cytochrome P-450s or other macromolecular systems in the living organism can only be properly defined from experiments with the pure enantiomers, (2) an enantiomer of a racemic drug may contribute significantly to biological effect not by its inherent activity but by altering the pharmacokinetics of the eutomer, and (3) enantiomeric interactions are not easily detected unless directly sought and may be relatively common.
Kunze
K L
KL
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
Eddy
A C
AC
Gibaldi
M
M
Trager
W F
WF
D001189:Aryl Hydrocarbon Hydroxylases; D065729:Cytochrome P-450 CYP2C9; D065607:Cytochrome P-450 Enzyme Inhibitors; D006801:Humans; D007700:Kinetics; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D013237:Stereoisomerism; D014859:Warfarin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D065607:Cytochrome P-450 Enzyme Inhibitors; D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases