The stereoselective effects of bucolome on the pharmacokinetics and pharmacodynamics of racemic warfarin

The objective of this study was to investigate the stereoselective influenc e of bucolome on the pharmacokinetics and pharmacodynamics of warfarin in J apanese inpatients with heart disease. Thirty patients were administered a fixed maintenance dose of warfarin alone once a day for at least 7 days. Th e other 25 patients were concomitantly administered warfarin and a 300 mg d ose of bucolome once a day, and blood samples were collected on days 1, 4, 7, 14, or 21 after administration of bucolome. Serum concentration of warfa rin enantiomers was measured by a chiral reversed-phase HPLC-ultraviolet de tection method. The PT-INR was used os a measure of the pharmacodynamic eff ect of warfarin. Coadministration of bucolome and warfarin had no effect on serum (R)-warfarin concentration and significantly increased serum (S)-war farin concentration compared with warfarin alone. The PT-INR of warfarin al one was significantly lower with bucolome cotreatment. These results indica te that the augmented anticoagulant effect of warfarin rin by bucolome is d ue to inhibition of (S)-warfarin metabolism in vivo. When bucolome is added to a stabilized regimen of warfarin therapy, the dose of warfarin should b e reduced by about 30% to 60%, and caution should be exercised during the f irst 7 days after coadministration of bucolome. (C) 2001 the American Colle ge of Clinical Pharmacology.