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The warfarin‐sulfinpyrazone interaction: stereochemical considerations
Author(s) -
Toon Stephen,
Low Lawrence K,
Gibaldi Milo,
Trager William F,
O'Reilly Robert A,
Motley Catherine H,
Goulart Darklis A
Publication year - 1986
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.1986.3
Subject(s) - sulfinpyrazone , warfarin , hypoprothrombinemia , chemistry , pharmacology , urine , drug interaction , pharmacokinetics , probenecid , cyp2c9 , prothrombin time , metabolism , medicine , biochemistry , atrial fibrillation , cytochrome p450 , aspirin , vitamin k
To allow the simultaneous evaluation of the interaction between sulfinpyrazone and each enantiomer of racemic warfarin, pseudoracemic warfarin (1:1 12 C‐ R (+) and 13 C‐ S (−)warfarin) was given to six normal subjects both before and during oral sulfinpyrazone dosing. Serial blood and urine samples were analyzed for unchanged warfarin and its metabolic products by GC/MS. A mass balance of an oral dose of pseudoracemic warfarin, containing a tracer quantity of 14 C‐warfarin, was carried out in one of the subjects by monitoring 14 C levels in urine and feces for 15 days. Concomitant sulfinpyrazone dosing markedly increased hypoprothrombinemia, decreased clearance of (S) ‐warfarin, and increased clearance of (R) ‐warfarin. Sulfinpyrazone also decreased the urinary excretion of warfarin‐related products but increased their fecal excretion by an equivalent amount. Virtually all of the administered warfarin dose could be accounted for either as unchanged drug or known metabolites. Pharmacokinetic analysis of the data suggests the following: At least four distinct enzymes (two oxidases and two reductases) are involved in the metabolism of warfarin. Sulfinpyrazone increases the hypoprothrombinemia caused by warfarin primarily by inhibition of the cytochrome P‐450–mediated oxidation of (S) ‐warfarin, the biologically more potent enantiomer. The increased clearance of (R) ‐warfarin results not from induction, but from its selective displacement from plasma protein binding sites. Clinical Pharmacology and Therapeutics (1986) 39, 15–24; doi: 10.1038/clpt.1986.3