Binding of nonsteroidal anti-inflammatory agents and their effect on binding of racemic warfarin and its enantiomers to human serum albumin.
The binding of racemic warfarin, its enantiomers, and several nonsteroidal anti-inflammatory agents to human serum albumin was investigated by equilibrium dialysis at 4 degrees C in pH 7.4 phosphate buffer. The primary binding constant for the S(-) enantiomer of warfarin was approximately two times greater than the corresponding binding of the R(+) enantiomer. The effect of azapropazone, phenylbutazone, naproxen, ibuprofen, mefenamic acid, and tolmetin on the binding of racemic warfarin and its enantiomers was studied. Warfarin was displaced by all of the nonsteroidal anti-inflammatory agents except tolmetin. Azapropazone caused the largest displacement of warfarin (39 to 46% free warfarin versus 2.5 to 6% free warfarin without competing drug), followed by phenylbutazone (23 to 43% free warfarin), naproxen (9 to 24% free warfarin), mefenamic acid (5 to 11.5% free warfarin), and ibuprofen (5 to 9% free warfarin). Azapropazone and phenylbutazone competed with warfarin for the same primary binding site on the albumin molecule. Naproxen appeared to affect warfarin binding at both primary and secondary sites. Ibuprofen and mefenamic acid interfered with the binding of warfarin at its secondary sites. In contrast to the other drugs studied, tolmetin caused an increase in the primary binding constant of warfarin. Structural analysis indicated that a common feature of those compounds which primarily bind at the warfarin site is a hydrophobic area bearing a widely delocalized negative charge.
Diana
F J
FJ
E.I. du Pont de Nemours & Company, Wilmington, DE 19898.
Veronich
K
K
Kapoor
A L
AL
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism* / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003956:Dialysis; D006801:Humans; D011485:Protein Binding; D012710:Serum Albumin, Bovine / Q000378:metabolism; D013237:Stereoisomerism; D014859:Warfarin / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D012710:Serum Albumin, Bovine; D014859:Warfarin