To allow the simultaneous evaluation of the interaction between
sulfinpyrazone and each enantiomer of racemic
warfarin, pseudoracemic
warfarin (1:1 12C-R(+) and 13C-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 14C-warfarin, was carried out in one of the subjects by monitoring 14C 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.