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

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