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

• Published in: British journal of clinical pharmacology Vol. 35; no. 3; pp. 327 - 330
• Main Authors: Hallak, HO, Wedlund, PJ, Modi, MW, Patel, IH, Lewis, GL, Woodruff, B., Trowbridge, AA
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.03.1993; Blackwell Science
• Subjects: Adult; Biological and medical sciences; Blood Coagulation - drug effects; Blood. Blood coagulation. Reticuloendothelial system; Drug Resistance; Female; Humans; Male; Medical sciences; Pharmacology. Drug treatments; Stereoisomerism; Vitamin K - pharmacokinetics; Vitamin K 1 - analogs & derivatives; Vitamin K 1 - pharmacokinetics; Warfarin - administration & dosage; Warfarin - pharmacokinetics; Warfarin - pharmacology; Case study; Human; Antivitamin K; Pharmacogenetics; Sensitivity resistance; Structure activity relation; Stereospecificity; Anticoagulant; Pharmacokinetics; Optical isomer
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/j.1365-2125.1993.tb05703.x

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).