High clearance of (S)‐warfarin in a warfarin‐resistant subject.

A 30 year old black male required a 60 mg daily dose of warfarin to elicit a therapeutic anticoagulant response (normal warfarin dose 2.5‐ 10 mg day‐1; maximum 15 mg day‐1). Hereditary warfarin resistance was suspected after compliance, diet, concurrent medication and any gastrointestinal disorder were eliminated as contributory causes. The disposition of vitamin K and vitamin K epoxide was examined in the propositus, his two sisters and 13 control black male subjects. Each subject was given an i.v. bolus dose (5 mg) of vitamin K prior to and after 2 weeks of warfarin therapy (5 mg day‐1). The oral clearances of (S)‐ and (R)‐warfarin were also measured in each subject during the last day of warfarin therapy. The mean (+/‐ s.d.) systemic clearance of vitamin K was similar in all subjects before (114 +/‐ 35 ml min‐1) and after (112 +/‐ 40 ml min‐1) warfarin therapy. The mean (+/‐ s.d.) AUC value for vitamin K epoxide was increased by warfarin treatment (6.5 +/‐ 5.4 micrograms ml‐1 min before and 139 +/‐ 78 micrograms ml‐1 min after) in all subjects. In the propositus, the oral clearance of (S)‐ warfarin (14.5 ml min‐1) and the clearance ratio for (S)/(R)warfarin (2.6) differed by more than 7 standard deviations from the control group (4.3 +/‐ 1.1 ml min‐1 and 1.2 +/‐ 0.2, respectively). In one sister of the propositus, the stereoselective disposition of warfarin was comparable with that of her brother ((S)‐warfarin clearance = 16.2 ml min‐1; and (S)/(R)‐warfarin clearance ratio = 2.7).