Binding of a metabolite of triflusal (2-hydroxy-4-trifluoromethylbenzoic acid) to serum proteins in rat and man

Summary

2-hydroxy-4-trifluoromethylbenzoic acid (HTB) is the main active metabolite of the platelet anti-aggregant drug triflusal. Its binding to plasma proteins of rats and healthy volunteers in vitro and in vivo has been studied.

Rats were given a single oral dose of 50 mg·kg⁻¹ triflusal and the healthy volunteers received 300 mg as a single oral dose or a multiple dose regimen of 600 mg every 24 h and 300 mg every 8 h, both for 13 days. Protein-free HTB was obtained by ultrafiltration. Unbound and total HTB concentrations were determined by HPLC.

HTB was primarily bound to albumin in plasma. The Scatchard plots suggested two types of binding sites for HTB on the albumin molecule. In rats, the binding constants (K=intrinsic affinity constant, n=number of binding sites) were K₁=1.4×10⁵ l·mol⁻¹, n₁=1.23, and K₂=4.1×10³ l·mol⁻¹ and n₂=3.77. The mean plasma concentration in rats after oral administration was 185 (37) μg·ml⁻¹ (protein-free HTB: 2.44 (0.77)%). The binding constants in human plasma were K₁=4.7×10⁵ l·mol⁻¹, n₁=1.93, K₂=4.3 l·mol⁻¹ and n₂=4.28.

The plasma HTB concentration in man (n=8) was 35 μg·ml⁻¹ (C_max) after a single oral dose of triflusal 300 mg, 172.96 μg·ml⁻¹ (C_max·ss) during the multiple dosage regimen of 300 mg every 8 h, and 131 μg·ml⁻¹ (C_max·ss) during the multiple oral dose regimen of 600 mg every 24 h. Unbound HTB ranged from 0.27 to 0.43%, depending on dose. HTB had high affinity for plasma albumin, which was not saturable after therapeutic doses. It showed linear elimination.