Protein binding of tolmetin

Area of Science:

• Pharmacology
• Biochemistry
• Drug Metabolism

Background:

• Tolmetin is a nonsteroidal anti-inflammatory agent.
• Understanding drug-protein binding is crucial for pharmacokinetics and efficacy.
• Human serum albumin (HSA) is a primary binding protein in plasma.

Purpose of the Study:

• To investigate the protein binding of tolmetin to HSA and human plasma.
• To determine the effect of concentration on tolmetin binding.
• To assess the influence of other substances on tolmetin-HSA interactions.

Main Methods:

• Equilibrium dialysis and ultrafiltration were used to study 14C-tolmetin binding.
• Binding was assessed at various tolmetin concentrations and to different HSA concentrations (4% and 0.4%).
• The impact of co-administered drugs, a metabolite (McN 2987), tryptophan, and oleic acid was evaluated.

Main Results:

• At therapeutic concentrations (3.0-28.7 microgram/ml), unbound tolmetin in 4% HSA was ~0.3%.
• Tolmetin exhibited three classes of binding sites on 0.4% HSA, with binding being largely entropic for high-affinity sites.
• Aspirin and salicylic acid synergistically decreased tolmetin binding; oleic acid markedly increased it. McN 2987 and tryptophan showed slight decreases. Binding was lower in arthritic patients' plasma.
• Tolmetin was not significantly taken up by red blood cells at therapeutic concentrations.

Conclusions:

• Tolmetin exhibits concentration-dependent protein binding to HSA, with a low unbound fraction at therapeutic levels.
• Plasma protein binding of tolmetin is primarily to albumin.
• Co-administered substances can significantly modulate tolmetin binding, potentially affecting its therapeutic efficacy and safety profile.