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The mechanism of the interaction between amiodarone and warfarin in humans
Author(s) -
Heimark Larry D,
Wienkers Larry,
Kunze Kent,
Gibaldi Milo,
Eddy A Craig,
Trager William F,
O'Reilly Robert A,
Goulart Darklis A
Publication year - 1992
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1992.39
Subject(s) - warfarin , amiodarone , pharmacology , microsome , drug interaction , metabolite , chemistry , hydroxylation , cyp2c9 , in vivo , pharmacokinetics , metabolism , cytochrome p450 , in vitro , medicine , atrial fibrillation , biochemistry , enzyme , biology , microbiology and biotechnology
Amiodarone decreased the total body clearance of both (R)‐ and (S)‐warfarin in normal subjects but did not change volumes of distribution. Warfarin excretion products were quantified and clearance and formation clearance values calculated. Amiodarone and metabolites inhibited the reduction of (R)‐warfarin to (R,S)‐warfarin alcohol‐1 and the oxidation of both (R)‐ and (S)‐warfarin to phenolic metabolites. Inhibition of warfarin hydroxylation by amiodarone in human liver microsomes was compared with the in vivo results. In agreement, the in vitro data indicates that amiodarone is a general inhibitor of the cytochrome P450 catalyzed oxidation of both enantiomers of warfarin, but the metabolism of (S)‐warfarin is more strongly inhibited than that of (R)‐warfarin. These data suggest that the enhanced anticoagulant effect observed when amiodarone and warfarin are coadministered is attributable to inhibition of P4502C9, the isozyme of P‐450 primarily responsible for the conversion of (S)‐warfarin to its major metabolite, (S)‐7‐hydroxywarfarin. Clinical Pharmacology and Therapeutics (1992) 51, 398–407; doi: 10.1038/clpt.1992.39