The research of pharmacokinetic parameters and metabolism of sodium 2-((4-amino-5-(thiophen-2-ylmethyl)-4h-1,2,4-triazol-3-yl)thio)acetate for use in military and civilian medicine

Abstract

Introduction. Chromatographic methods are often used in the study of pharmacokinetic parameters. Thus, the aim of the study was to investigate the pharmacokinetic parameters and metabolism of sodium 2-((4-amino-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)acetate (ASP) as a potential active pharmaceutical ingredient with high rates of proven acto- and stress-protective effects, which can be recommended for use in military and civilian medicine. The aim of the study is to investigate the pharmacokinetic parameters and metabolism of sodium 2-((4-amino-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)acetate (ASP) in the blood serum of rats by intragastric administration. Materials and methods. Blood sampling of experimental animals was carried out within 24 hours with intervals of 0.25, 0.75, 2.5, 7.5, 13.5 and 24 hours. Approval of the ethics committee № 6 of 08.06.2021. The obtained plasma was used to determine the concentration of ASP (chromatographically) and identify possible metabolites (mass spectrometrically). To evaluate the pharmacokinetic properties of ASP, the following data were calculated: area under the pharmacokinetic curve "concentration-time" (AUC), total clearance (cl), the constant elimination (Kel), volume (Vd), period elimination half-life (T1/2). Results. The analysis of the main pharmacokinetic parameters of sodium 2-((4-amino-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)acetate (ASP) by intragastric introduction to rats was held. For oral use AUC is 3.7088 μgh/ml. The half-life (T1/2) is 6.06 hours. The following possible metabolic products were predicted for phase II biotransformation. This is a reaction of O-glucuronation of an aliphatic acid, formation of a thioester through S-methylation, and possible formation of a glycine conjugate. And also carnitine conjugation (based on a collection of enzymes). Analysis of the pseudomolecular ion peak shows the possible formation of a glycine conjugate corresponding to the structure predicted in BioTransformer. The presence of O-glucuronide as a metabolite was confirmed by PLS DA VIP score and t-test analysis. Conclusions. As a result, the main pharmacokinetic parameters (AUC, cl, Kel, Vd, T1/2) and metabolism (formation of thioether, formation of conjugate of glycine and O-glucuronide) of sodium 2-((4-amino-5-(thiophene)-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)acetate (ASP) in the blood serum of rats was studied.

Keywords

• 1,2,4-triazole, HPLC-MS, metabolism, biotransformation prediction.