Fraction Of Warfarin Research Articles

Phenylbutazone-warfarin interaction in the dog.

The administration of phenylbutazone together with warfarin to dogs resulted in an elevation of the free fraction of warfarin in the plasma from 2-6 to 8-0% thus providing direct support for the notion that phenylbutazone induced inhibition of warfarin binding to plasma proteins. This inhibition as evaluated by a kinetic method was accompanied by a two-fold decrease in the plasma half-life of warfarin from 18-4 h in control animals to 9-6 h in phenylbutazone-treated animals. Marked increases in warfarin-induced hypoprothrombinaemia were observed when at doses up to 8 mg kg-1 (orally) it was given with phenylbutazone (50 mg kg-1, orally). The unbound fraction of warfarin in canine plasma ranged from 1-7 to 4-3% indicating individual differences in the extent of the plasma binding of warfarin in the dog.

Interethnic differences in drug protein binding and alpha 1 acid glycoprotein concentration.

Interethnic differences in drug responsiveness may in part be accounted for by differences in drug disposition. We investigated the reversible binding interaction by equilibrium dialysis between a representative acidic (warfarin) and basic (lignocaine) drug and drug binding proteins in 20 healthy age and sex matched Iranian and Irish (Caucasian) subjects. The unbound fraction of warfarin and its major binding protein albumin, were similar in the two groups. In contrast unbound lignocaine was higher in Iranian subjects (49.6 +/- 6.96 vs 37.7 +/- 51%, mean +/- SD, p < 0.05) and this was associated with lower plasma concentrations of alpha 1 acid glycoprotein (AAG, 48.8 +/- 10 vs. 60.5 +/- 8 mg/dl p < 0.01) Such alterations may result in differences in drug responsiveness in addition to predictable pharmacokinetic consequences. Protein binding should be included in comparative studies of drugs in subjects of different races.

Effect of Late Pregnancy on Salicylate, Diazepam, Warfarin, and Propranolol Binding

Serum protein binding was measured in six women 38 wk pregnant and in five control subjects. Three distinct binding sites for drugs on human serum albumin have been identified. To determine whether changes in binding during pregnancy occur for common drugs or only for drugs that bind to a specific binding site, serum protein binding of three drugs—diazepam (site I), warfarin (site III), and salicylate—and four fluorescent probes—dansylsarcosine (site I), l-anilino-8-naphthalenesulfonate (site I), 7-anilinocoumarin-4-acetic acid (site II), and 5-dimethylaminonaphthalene-1-sulfonamide (DNSA) (site III)—were determined in control and pregnant sera. Unbound fractions of diazepam and salicylate in pregnant women increased but the unbound fraction of warfarin did not change. Dissociation constants (Kd1) of all fluorescent probes but DNSA were almost the same in control and pregnant sera, while the Kd1 of DNSA in pregnant serum was approximately 50% of control. Binding capacities of all probes decreased, which was attributed to decreased serum albumin concentration. We concluded that serum protein binding of drugs that bind to site I or site II on albumin decreased largely because of the reduced serum albumin concentration during pregnancy and that the binding of drugs that bind to site III changed little because of compensating effects of the decrease in serum albumin concentration and the increase in binding affinity to serum albumin. Serum concentration of α1-acid glycoprotein and serum binding of propranolol did not change in pregnant women. Clinical Pharmacology and Therapeutics (1984) 36, 201–208; doi:10.1038/clpt.1984.163