Triflusal

Triflusal reduces thromboxan biosynthesis through irreversible inhibition of platelet cyclooxygenase, sparing prostacyclin biosynthesis because its effect on vascular cyclooxygenase at therapeutic doses is negligible. On the other hand, the main triflusal metabolite, 2-hydroxy-4-(trifluoromethyl)benzoic acid (HTB), is a reversible platelet cyclooxygenase inhibitor and, because of its long elimination half-life (approximately 34 h), contributes to the antiplatelet activity of triflusal. Both triflusal and HTB are able to increase the concentration of cyclic adenosine 5-monophosphate (cAMP) in platelets through inhibition of platelet phosphodiesterases. In addition, triflusal has been shown to stimulate in vitro and ex vivo nitric oxide release in human neutrophils, which also contributes to the antiplatelet effect.

Triflusal has been shown to inhibit platelet aggregation in both healthy volunteers and patients. In ex vivo studies, triflusal inhibited by 65% the platelet aggregation induced by arachidonic acid in plateletrich plasma (PRP) from healthy volunteers 24 hours after administration of a single 600 mg dose. Repeated triflusal administration (600 mg/day for 7 days) caused a 50%-75% inhibition of platelet aggregation (PRP) induced by arachidonic acid, ADP (adenosine diphosphate), epinephrine, or collagen.

Triflusal is rapidly absorbed (t_1/2 Ka = 0.44 h), and has an absolute bioavailability of 83%-100%. Triflusal is rapidly metabolised by the action of esterases to its main metabolite, HTB, which is also active. In urine, a secondary metabolite was identified as a HTB-glycine conjugate. Plasma half-life (t_1/2) was 0.53 ± 0.12 h for triflusal and 34.3 ± 5.3 h for HTB. Elimination preferentially occurs through renal excretion (renal clearance >60% at 48 hours). Unchanged triflusal, HTB, and the HTBglycine conjugate were detected in urine.

Following administration of a single oral dose of triflusal 300 mg or 900 mg to healthy volunteers, mean triflusal peak plasma concentrations (C_max) were 3.2 ± 1.9 g/mL and 11.6 ± 1.7 g/mL respectively, while the C_max for HTB reached 36.4 ± 6.1 g/mL and 92.7 ± 17.1 g/mL. Time to C_max (t_max) was 0.88 ± 0.26 h for triflusal and 4.96 ± 1.37 h for HTB at the 900 mg dose. HTB pharmacokinetic parameters after repeated administration (triflusal 300 mg three times daily or 600 mg once daily for 13 days) showed steady state peak plasma concentrations (C_maxss) of HTB of 178 ± 42 g/mL and 153 ± 37 g/mL respectively.

At therapeutic concentrations, HTB has a plasma albumin binding rate of 98%-99%. This binding was not significantly altered by the presence of caffeine, theophylline, glisentide, enalapril, cimetidine, or warfarin. However, HTB free fraction significantly increased in the presence of non-steroidal antiinflammatory drugs (NSAIDs) such as diclofenac, ibuprofen, indomethacin, naproxen, piroxicam. or salicylic acid. At high concentrations, HTB displaced NSAIDs, glisentide, and warfarin from their protein binding sites. These agents have affinity for the same albumin binding sites and may displace each other as a function of their affinities for the protein and the total concentration of the displacing agent.

Special populations

In elderly volunteers, steady state plasma concentrations of triflusal and HTB were reached 3 to 5 days after administration of triflusal 300 mg twice daily. Values of AUCss, C_max, and t_max in elderly volunteers were not significantly different from those reported in young volunteers. Plasma half-lives (t_1/2) were 0.92 ± 0.16 h for triflusal and 64.6 ± 6.6 h for HTB. However, this increase has no clinical relevance warranting dose adjustment in elderly subjects.

In patients with end-stage chronic renal disease on conventional haemodialysis, HTB plasma concentrations measured before and after dialysis were similar.

Preclinical data revealed no special risk for humans, according to the results of conventional safety pharmacology, repeated administration toxicity, genotoxicity, and reproductive toxicity studies.

After long-term administration of triflusal to rats and dogs (10, 25, and 50 mg/kg/day for 12 months), biochemical, morphological, and histopathological changes were only found at the high dose. The most significant pathological signs were gastrointestinal intolerance, including gastric ulcers, moderate anaemia, vomiting (in dogs), slight changes in organ weight (liver, kidneys, heart, and spleen), and mild to moderate nephrosclerosis. Most of these effects, except for nephrosclerosis, were reversible 13 weeks after treatment discontinuation.