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The warfarin-sulfinpyrazone interaction: stereochemical considerations.

S Toon, L K Low, M Gibaldi

Clinical Pharmacology and Therapeutics

|January 1, 1986

Summary

Sulfinpyrazone enhances warfarin's anticoagulant effect by inhibiting the metabolism of its more potent S-enantiomer. This drug interaction increases hypoprothrombinemia and alters warfarin clearance and excretion pathways.

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Area of Science:

Pharmacology
Drug Metabolism
Toxicology

Background:

Warfarin is a widely used anticoagulant with complex enantioselective metabolism.
Sulfinpyrazone is a uricosuric agent known to interact with drug metabolism pathways.

Purpose of the Study:

To investigate the pharmacokinetic interaction between sulfinpyrazone and warfarin enantiomers.
To elucidate the mechanisms by which sulfinpyrazone affects warfarin's disposition and anticoagulant activity.

Main Methods:

Administration of pseudoracemic warfarin (12C-R(+) and 13C-S(-)) to healthy subjects before and during sulfinpyrazone treatment.
Analysis of warfarin and its metabolites in blood and urine using Gas Chromatography/Mass Spectrometry (GC/MS).
Mass balance study using 14C-warfarin to track excretion over 15 days.

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Main Results:

Sulfinpyrazone significantly increased hypoprothrombinemia and decreased the clearance of (S)-warfarin.
Clearance of (R)-warfarin was increased, attributed to displacement from plasma protein binding.
Sulfinpyrazone altered excretion patterns, decreasing urinary and increasing fecal elimination of warfarin metabolites.

Conclusions:

Sulfinpyrazone inhibits cytochrome P-450-mediated oxidation of (S)-warfarin, the primary driver of increased hypoprothrombinemia.
The interaction involves multiple metabolic enzymes and affects both warfarin enantiomers differently.
Understanding these interactions is crucial for managing anticoagulant therapy.