Stereoselective Interaction of Phenylbutazone with [12C/13C]Warfarin Pseudoracemates in Man

Abstract

A B S T R A C T To evaluate the interaction of phenylbutazone with racemic warfarin or R,S-(±)-warfarin in man, S-(-)-warfarin or levowarfarin was synthesized with 13C label in the 2-position of the coumarin nucleus and added to [12C]R(+)-warfarin or dextrowarfarin to fonri a [12C/13C]pseudoracemiiate of warfarin. In six normal human subjects, a single oral dose of this "cold labeled" pseudoraceemate, 1.5 mg/kg body weight, was administered with and without a daily dosage of phenylbutazone, 300 milg orally, beginning 3 d before the warfarin dose and continuing throughout the hypoprothrombinemia. Plasma samples were obtained daily and analyzed for warfarin content and for onestage prothrombin activity. Unchanged warfarin in the plasma was fractionate(d by normal-phase, high-pressure liquid chromatography, and the enantiomorphic ratios were determined by chemical-ionizationi mass spectrometry with pentadeuteriowarfarin as the internal standard. A highly significanit augmnentation of the hypoprothrombinemia of the pseudoracemate occurred during the phenylbutazone regimen (P < 0.001) compared with pseudoracemiiic warfarin adminiistered alone. There was a highly significant increase in the plasmna clearance of dextrowarfarin (P < 0.01) and a significant decrease in the plasma clearanice of levowarfarin (P < 0.05) during the phenylbutazone regimen compared with administration of warfarin alone. It was concluded that phenylbutazonie augmented the hypoprothrombinemnia of pseudoracemic warfarin stereoselectively by inhibiting the metabolic disposition of the imore hypoprothrombinemiiic levowarfarin, yet reduced the plasma levels of pseudoPortions of this work were presented at the 37th Anntual Meeting of the Federation of Amiierican Society of Experimental Biology, Atlantic City, N. J., 10 April 1978 anid have been publishecl in abstract form in 1978. Fed. Proc. 37: 545.

Phenylbutazone‐warfarin interaction in man: further stereochemical and metabolic considerations.

“…The study has been described previously (O'Reilly et al, 1980), and involved oral administration of 1.5 mg/kg of racemic warfarin to volunteers before and 4 days into a 12-day oral regimen of 100 mg phenylbutazone three times a day, with a 4-week rest period between the two phases. The study was approved by the local ethical committee and the results reported below were obtained in three healthy volunteers who gave their informed consent.…”

American Heart Association/American College of Cardiology Foundation Guide to Warfarin Therapy

“…25,26 Inhibition of S-warfarin metabolism is more important clinically because this isomer is 5 times more potent than the R-isomer as a vitamin K antagonist. 25,26 Phenylbutazone, 27 sulfinpyrazone, 28 metronidazole, 29 and trimethoprimsulfamethoxazole 30 inhibit clearance of S-warfarin, and each potentiates the effect of warfarin on the prothrombin time (PT). In contrast, drugs such as cimetidine and omeprazole, which inhibit clearance of the R-isomer, potentiate the PT only modestly in patients treated with warfarin.…”

Enantiomeric drug development: Issues, considerations, and regulatory requirements

“…24,25 However, the S-enantiomer is 3±4 times more potent than the R-enantiomer in its anticoagulant property. 24,25 One of the signi®cant problems associated with the use of warfarin is related to the risk of hemorrhage. This risk will not be reduced by using either the more active enantiomer or the less active enantiomer.…”