Interaction of secobarbital with warfarin pseudoracemates

Abstract

To evaluate the interaction of secobarbital with racemic warfarin or R,S(+/-)-warfarin, S(-)-warfarin was synthesized with 13C-label in the 2-position of the coumarin nucleus and added to 12C-R(+)-warfarin to form a 12C-/13C-warfarin pseudoracemate. Six normal subjects received 1.5 mg/kg of this "cold-labeled" pseudoracemate. It was given with and without a daily oral dose of secobarbital, 100 mg, beginning 7 days before the warfarin and continuing throughout the hypoprothrombinemia. Plasma samples were obtained daily and analyzed for warfarin and for one-stage prothrombin activity. Unchanged warfarin in plasma was fractionated by forward-phase high-pressure liquid chromatography, and enantiomorphic ratios were determined by chemical ionization-mass spectrometry with pentadeuterio-warfarin as the internal standard. There was a reduction of the hypoprothrombinemia of the pseuoracemate during the secobarbital regimen over that on warfarin alone (p < 0.001). There was an increase in plasma clearance of R-warfarin (p < 0.05) and an increase in plasma clearance of S-warfarin (p < 0.003) during the secobarbital regimen over that on warfarin alone. It was concluded that secobarbital diminished the hypoprothrombinemia of pseudoracemic warfarin by increasing plasma clearance of the more hypoprothrombinemic S-warfarin and by increasing plasma clearance of the less hypoprothombinemic R-warfarin.