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

Abstract

2-hydroxy-4-trifluoromethylbenzoic acid (HTB) is the main active metabolite of the platelet antiaggregant 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 x 10(5) l.mol-1, n1 = 1.23, and K2 = 4.1 x 10(3) l.mol-1 and n2 = 3.77. The mean plasma concentration in rats after oral administration was 185 (37) micrograms.ml-1 (protein-free HTB:2.44 (0.77)%). The binding constants in human plasma were K1 = 4.7 x 10(5) 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 micrograms.ml-1 (Cmax) after a single oral dose of triflusal 300 mg, 172.96 micrograms.ml-1 (Cmax.ss) during the multiple dosage regimen of 300 mg every 8 h, and 131 micrograms.ml-1 (Cmax.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.(ABSTRACT TRUNCATED AT 250 WORDS)

Development and Validation of Rp-HPLC Method for the Estimation of Triflusal in Bulk and in Capsule Formulation

“…The detail literature survey revealed few analytical methods reported for evaluation TRI such as HPLC [3][4][5] . HPLC with automated column switching system 6 , spectroscopic and chromatographic characterization using supercritical impregnation technologies 7,8 .…”

Triflusal: An Antiplatelet Drug with a Neuroprotective Effect?

“…1), HTB differs chemically from salicylic acid (which is the metabolite of ASA) in the same way as their corresponding precursors. sively to plasma proteins, its blood levels are always higher than tissue levels (43,44,47,48). It has been recently found that the daily oral intake of 600 mg triflusal led to HTB levels in the cerebrospinal fluid that had neuroprotective effects in experimental animals (57).…”

“…In animals its excretion is mainly renal, with a urinary clearance of 60% at 48 h after intake (43,44,49,52). In urine, free HTB, glycine-conjugated HTB, and an unidentified metabolite with greater polarity than HTB (52) have been identified in addition to unchanged triflusal.…”

“…Unlike ASA, triflusal is less likely to interfere with the efficacy of antihypertensive drugs (42), especially ACE inhibitors (14,28). However, HTB interacts with serum protein binding of various drugs to the same degree as ASA, so that precautions must be taken when trifusal is used in combination with anticoagulants (43,44).…”

Hydrophilic Polymer Drug from a Derivative of Salicylic Acid: Synthesis, Controlled Release Studies and Biological Behavior

“…The hydrolytical behavior was followed by the analysis of the active metabolite HTB because of the well-known instability of TRF in aqueous media. [12] Drug release was monitorized by means of an HPLC method. The analysis was performed by using a mixture (60:40) of methanol/water solution of PIC A (a solution of tetrabutylammoniumhydrogen sulphate in water, supplied by Waters) as the mobile phase and a flow rate of 1 mL Á min À1 .…”