Excretion Study of 5-[5-(Trifluoromethyl)-1,2-oxazole-3-yl]-furan-2-sulfonamide in Rats

INTRODUCTION. The administration of 5-[5-(trifluoromethyl)-1,2-oxazole-3-yl]-furan-2-sulfonamide (TFISA) into the eyes can reduce intraocular pressure. Currently, this novel selective carbonic anhydrase II inhibitor is at the preclinical research stage. The excretion of TFISA and its metabolites has not been studied yet.

AIM. This study aimed to calculate the parameters of urinary and faecal excretion of TFISA and its major metabolites in rats.

MATERIALS AND METHODS. The study was performed in 6 Wistar rats (3 males and 3 females). The rats received an instillation of 1% TFISA ophthalmic suspension in each eye at a dose of 3.7 mg/kg. Stool samples were taken prior to TFISA administration and at multiple intervals up to 360 h afterwards. Excreta were collected using metabolic cages. The study used high-performance liquid chromatography with tandem mass spectrometry (HPLC–MS/MS) to measure the concentrations of TFISA, N-acetyl-5-[5-(trifluoromethyl)-1,2-oxazole-3-yl]-furan-2-sulfonamide (M2), and N-hydroxy-5-[5-(trifluoromethyl)-1,2-oxazole-3-yl]-furan-2-sulfonamide (M1) with its degradation product 5-[5-(trifluoromethyl)-1,2-oxazole-3-yl]-furan-2-sulfonic acid (M3) in the excreta.

RESULTS. The study involved full validation of bioanalytical procedures for the determination of TFISA and its metabolites in rat excreta. The analytical ranges were 10–10,000 ng/mL for the urinary levels of TFISA, M2, and M3; 1–1,000 ng/mL for the urinary levels of M1; 10–4,000 ng/g for the faecal levels of TFISA; 5–2,000 ng/g for the faecal levels of M2 and M3; and 1–1000 ng/g for the faecal levels of M1. Out of the total amount eliminated, 45.7±2.0% of unchanged TFISA, 38.7±2.7% of TFISA in the form of M1 and its degradation product M3, and 4.0±0.6% of TFISA in the form of M2 were excreted in urine, while 8.2±1.0% of unchanged TFISA and 3.3±0.2% of the N-hydroxy metabolite M3 were excreted in faeces. TFISA elimination continued for up to 336 h after administration.

CONCLUSION. The developed and successfully validated bioanalytical procedures were used to study the excretion of TFISA and its metabolites in rats after single-dose administration of the ophthalmic TFISA suspension. According to the results, TFISA is predominantly excreted unchanged in urine. In addition, TFISA is eliminated as its N-hydroxy metabolite, which almost completely degrades to the sulfonic acid derivative during the sampling process. The N-acetyl metabolite of TFISA is minor and is exclusively excreted in urine.

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