The pharmacokinetics and pharmacodynamics of single dose (R)‐ and (S)‐warfarin administered separately and together: relationship to VKORC1 genotype

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The contribution of (S)-warfarin to the clinical effect of rac-warfarin is well understood. The extent to which (R)-warfarin contributes to the clinical effect of rac-warfarin is unclear. WHAT THIS STUDY ADDS• Using unequivocally pure (R)-and (S)-warfarin we have demonstrated that (R)-warfarin contributes to the hypoprothrombinaemic effect of single large doses of warfarin.• The extent of the interaction is dependent on VKORC1 genotype. AIMS1) To determine the pharmacokinetics and pharmacodynamics of (R)-and (S)-warfarin given alone and in combination and 2) to determine whether the relative potency of (R)-and (S)-warfarin is dependent on VKORC1 genotype. METHODSA three way crossover study was conducted in which 17 healthy male subjects stratified by VKORC1 1173 C>T genotype and all CYP2C9 1*/1* received (R)-warfarin 80 mg, (S)-warfarin 12.5 mg and rac-warfarin sodium 25 mg. Plasma (R)-and (S)-warfarin unbound and total concentrations and prothrombin time were determined at multiple time points to 168 h. RESULTSPharmacokinetic parameters for (R)-and (S)-warfarin were similar to the literature. (R)-warfarin 80 mg alone resulted in a mean AUCPT (0,168 h) of 3550 s h (95% CI 3220, 3880). Rac-warfarin sodium 25 mg containing (S)-warfarin 11.7 mg produced a greater effect on AUCPT (0,168 h) than (S)-warfarin 12.5 mg (mean difference 250 s.h, 95% CI 110, 380, P < 0.002) given alone. In a mixed effects model the ratio of response between (R)-and (S)-warfarin (AUCPT((R)-warfarin) : AUCPT((S)-warfarin)) was 1.21 fold higher (95% CI 1.05, 1.41, P < 0.02) in subjects of VKORC1 TT genotype compared with the CC genotype. CONCLUSIONS(R)-warfarin has a clear PD effect and contributes to the hypoprothrombinaemic effect of rac-warfarin. VKORC1 genotype is a covariate of the relative R/S potency relationship. Prediction of drug interactions with warfarin needs to consider effects on (R)-warfarin PK and VKORC1 genotype.

Warfarin resistance associated with genetic polymorphism of VKORC1

“…Binding Site-1 shows selectivity for S-warfarin (Fig. 2b), although the ability of R-warfarin to also bind at this site (Table 1) is in agreement with the recent data of Maddison et al [30], who reported that R-warfarin contributes toward the anticoagulant response generated by a single dose of racwarfarin. Binding Site-2 binds both warfarin enantiomers with similar affinity ( Table 1).…”

Pharmacokinetic and pharmacodynamic drug–drug interaction assessment between pradigastat and digoxin or warfarin

“…CYP2C9, a polymorphic enzyme, is the principal form of human liver CYP450 that modulates the in vivo anticoagulant activity of warfarin . S warfarin is about twofold more active than R warfarin, but is eliminated more rapidly . The clearance of R warfarin is generally half that of S warfarin, thus as the volumes of distribution are similar, the half‐life of R warfarin is longer than that of S warfarin.…”

Characterization of Inhibition Kinetics of (S)-Warfarin Hydroxylation by Noscapine: Implications in Warfarin Therapy

“…Pooled HLMs (0.1 mg/ml) or recombinant enzymes (40 pmol/ml) were incubated with (S)-warfarin (2.5 mM) in the presence of noscapine (0-100 mM) in a NADPH-regenerating system for 20 minutes. The warfarin concentration was selected based on the apparent K m values in pooled HLMs or cDNA-expressed CYP2C9 (2-9 mM) (Liu et al, 2012) and the clinically relevant concentration range (C max , ;5 mM) (Maddison et al, 2013). 7-Hydroxywarfarin formation rates were determined, and the half-maximal inhibitory concentration (IC 50 ) values were estimated.…”