PHARMACOKINETICS OF TRIFLUSAL AND ITS MAIN METABOLITE IN RATS AND DOGS

The methods for determining plasma concentrations of triflusal (2-acet oxy-4-trifluoromethyl benzoic acid) that have been described, do not d istinguish between the drug and its main metabolite HTB (2-hydroxy-4-t rifluoromethyl benzoic acid). In the present study, we have developed a new analytical technique based on HPLC that enabled us to carry out a pharmacokinetic study of the drug and its metabolite in animals. An intravenous or oral dose of 50 mg/kg was administered to male Sprague- Dawley rats, and 15 mg/kg was administered to beagle dogs. Plasma leve ls of triflusal and HTB were determined. In rats, triflusal was quickl y eliminated from plasma with a biological half-life (t1/2) of 2.7 min and a clearance (Cl) of 73.4 (ml/kg)/min. The elimination of HTB was much slower with a t1/2 of 21.5 h and a Cl of 5.1 (mg/kg)/h. The maxim um concentration (C(max)) of triflusal in rats after an oral administr ation was 8.1 +/- 2.0-mu-g/ml reached between 2.5 and 10 min. The C(ma x) of HTB was 237.7-mu-g/ml and was achieved at 0.7 h. The bioavailabi lity of triflusal in rats was only 10.6% while the bioavailability of HTB was more than 100% indicating an important first pass effect. In d ogs the t1/2 of triflusal was 14.4 +/- 5.9 min and the Cl was 25.1 +/- 4.7 (ml/kg)/min. HTB was also eliminated very slowly with a t1/2 of 7 1.1 +/- 12.5 h and a Cl of 2.4 +/- 0.3 (ml/kg)/h. The C(max) of triflu sal in dogs was 13.3 +/- 2.9-mu-g/ml and was reached after 19.2 +/- 6. 1 min (t(max)). The C(max) of HTB was 54.6 +/- 5.7-mu-g/ml with a t(ma x) of 1.76 +/- 0.6 h. The bioavailability of triflusal and HTB was 83. 3 +/- 16.7% and 93.1 +/- 8.2%, respectively.