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Metabolic enantiomeric interactions: The inhibition of human (S)‐warfarin‐7‐hydroxylase by (R)‐warfarin
Author(s) -
Kunze Kent L.,
Eddy A. Craig,
Gibaldi Milo,
Trager William F.
Publication year - 1991
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.530030106
Subject(s) - chemistry , enantiomer , hydroxylation , warfarin , microsome , stereochemistry , cytochrome p450 , pharmacology , metabolism , enzyme , biochemistry , medicine , atrial fibrillation
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 K i s for inhibition of (S)‐6‐ and (S)‐7‐hydroxylation by (R)‐warfarin ranged from 7.0 to 8.4 μ M and from 6.0 to 6.9 μ M , respectively, while the K m s for the 6‐ and 7‐hydroxylation of (S)‐warfarin ranged from 3.6 to 3.8 μ M and from 3.3 to 3.9 μ M , 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.