warfarin and benzylthiouracil

The binding of drugs to human serum albumin determines the drug distribution through the systemic circulation and its pharmacological effects on the organism. Then, with the aim of obtaining information concerning the drug structural features which favour their binding on seroalbumin we have studied the seroalbumin binding to the heterocyclic drugs such as warfarin, propylthiouracil and cromoglycate and to similar compounds such as 4-hydroxy-coumarin, 3-acetylcoumarin, coumarin, benzylthiouracil, propyluracil, thiouracil, chromone and chromanol. These compounds were competitively displaced by warfarin at their primary binding sites on seroalbumin. The comparative analysis of the binding data showed that heterocyclic compounds such as benzopyranes (coumarins and chromanol) and benzyl pyrimidines with 4-hydroxyl groups bind specifically in the warfarin binding site. Then, 4-hydroxyl-bencene heterocycles will displace other ligands from the subdomain IIA of the seroalbumin molecule. Therefore, we can predict that the administration concomitant of warfarin, cromoglycate, propylthiouracil and analogous heterocyclic drugs involves the displacement of the drug without 4-hydroxyl and benzyl groups, increasing their free fraction in serum and the amount of active drug.

Topics: 4-Hydroxycoumarins; Benzopyrans; Binding, Competitive; Chromans; Humans; Kinetics; Protein Binding; Pyrimidines; Serum Albumin; Structure-Activity Relationship; Thiouracil; Warfarin

The binding interactions of some thioureylene compounds to human serum albumin were studied in vitro by ultraviolet spectroscopy and equilibrium dialysis. Binding of 6-n-propyl-2-thiouracil, 6-n-benzyl-2-thiouracil and 2-thiouracil to human serum albumin results in a red shift of the ultraviolet absorption maximum, suggesting that the binding site is a hydrophobic area of the protein. Bindings of 6-n-propyl-2-thiouracil and 6-n-benzyl-2-thiouracil to human serum albumin are characterized by two classes of sites while 6-n-propyl-uracil and 2-thiouracil bind to one low-affinity binding site. In addition, an identification of those sites was performed by measuring the displacement of these drugs. The data show that the moderate-affinity site is common with the warfarin site while the low-affinity site is likely to be shared by benzodiazepines. It is concluded that the binding is enhanced by the hydrophobicity of the substituent in the thioureylene compounds, and it is further shown that thiol-group substitutions in the thioureylene ring will weaken the binding.

Topics: Antithyroid Agents; Diazepam; Humans; Propylthiouracil; Serum Albumin; Spectrophotometry, Ultraviolet; Thiouracil; Uracil; Warfarin