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Protein binding of tolmetin
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1978
Year
Healthy SubjectsImmunologyQuantitative PharmacologyMolecular BiologyPharmacotherapyPharmacodynamic ModelingTranslational PharmacologyInflammationMolecular PharmacologyTolmetin BindingBioanalysisInflammatory MarkerClinical ChemistryProtein ChemistryProtein FunctionPharmacokinetic ModelingBiochemistryBiomolecular InteractionProtein BindingPharmacologyAnti-inflammatoryNatural SciencesClinical PharmacologyMedicinePharmacokineticsSalicylic Acid
The protein binding of the new nonsteroidal anti‐inflammatory agent tolmetin to human serum albumin (HSA) and to the plasma of 8 healthy subjects was studied by equilibrium dialysis at 37° and pH 7.4 with 14 C‐tolmetin. Over the total concentration (C t ) range 3.0 to 28.7 µg/ml (therapeutic range), the fraction oftolmetin unbound to 4% HSA was largely invariant at 0.3%. At 100 µg/ml the unboundfraction rose to 0.8 and at 434 µg/ml to 3.6%. Within the therapeutic concentration range, tolmetin binding to 0.4% HSA was reduced in accordance with the law of mass action and at C t = 26.2 µg/ml, 10.5% was free. Analysis of the 0.4% HSA data showed tolmetin had 3 classes of binding sites (n 1 = 1, K t = 8.3 × 10 5 M −1 ; n 2 = 4, K 2 = 2.4 × 10 4 M −1 ; n 3 = 44, K 1 = 7.9 × 10 1 M −1 ). By studying the binding to 0.4% HSA at 23°, it was established that the free energy change in binding for the first two classes of sites was entirely entropic in nature. Albumin accounted for almost all the binding oftolmetin in human plasma. The effect of other drugs, the tolmetin metabolite McN 2987 (5‐p‐carboxybenzoyl‐l‐methylpyrrole‐2‐acetic acid), tryptophan, and oleic acid on tolmetin binding to 4% HSA was studied using ultrafiltration and 14 C‐tolmetin. Aspirin and salicyclic acid decreased tolmetin binding and a combination of aspirin and salicylic acid exerted a synergistic displacing effect. Indomethacin and ibuprofen had no effect while phenylhbutazone and acetaminophen increased tolmetin binding slightly. Tolmetin binding was decreased slightly by McN 2987 and tryptophan and markedly increased by oleic acid. McN 2987 was not bound as extensively as tolmetin. Binding of 14 C‐tolmetin to the plasma of 4 arthritic patients was studied by ultrafiltration and found to be less than to normal plasma and 4% HSA. Distribution of tolmetin in the whole blood of 8 healthy subjects using a centrifugation technique showed that the drug was not taken up by red blood cells at therapeutic concentrations.