COMPARATIVE ASSESSMENT OF ANTI-HYPERGLYCEMIC AND ANTI-OXIDATIVE ACTIVIT Y OF METABOLITES OF THE SUCCINATE-CONTAINING ANTIDIABETIC DRUG
Keywords:metabolites of a succinate-containing antidiabetic medicine, anti-hyperglycemic and antioxidative activity
A new domestic antidiabetic medicine has been developed based on the β-phenylethylamide of 2-oxysuccinanil acid (β-PhEA-OSAA).
The main mechanism of its action embraces the oxidative stress inhibition, stimulation of the bioenergetic activity in mitochondria and decrease in non-enzymatic glycosylation. The first phase metabolites of β-PhEA-OSAA biotransformation are the 2-hydroxyphenylsuccinamide (2-HPhSA) and β-phenylethylsuccinamide (β-PhESA) which may play a certain part in mechanism of the antidiabetic action of this compound. The aim of our study was to evaluate the anti-oxidative and anti-hyper-glycemic potential of 2-hydroxyphenyl- and β-phenylethylsuccinamide compared to their parent compound, β-phenylethylamide of 2-oxysuccinanil acid.
The anti-hyperglycemic activeness of these compounds was determined in a glucose tolerance test in rats, which were orally introduced 2-HPhSA and β-PhESA in doses 17 mg/kg b.w. and 18 mg/kg b.w. These doses are equimolar to the effective dose of β- PhEA-OSAA, which is 25 mg/kg b.w. The glycemic level was assessed by parameters of the basal glycemia and the area under the glycemic curve. The study of the anti-oxidative activity of β-PhEA-OSAA metabolites was made in vitro using a suspension of yolk lipoproteins. We were determining the content of active compounds that react with the thiobarbituric acid in the system with an antioxidant and without it. The tested concentrations of compounds in the incubation medium were ranged from 25 μM to 500 μM. β-PhEA-OSAA served as a reference compound which was tested at the same concentrations.
We have found that 2-HPhSA and β-PhESA, as well as β-PhEA-OSAA, do not exhibit any anti-hyperglycemic activity in the glucose tolerance test.
Besides in vitro both of β-PhEA-OSAA metabolites proved to show a moderately expressed anti-oxidative effect which, under their combined influence, was enhanced and had an additive dependence within a certain concentration range. β-PhESA significantly exceeds the second metabolite by the degree of its antioxidant activity at the concentration range of 100-250 μM. However, both metabolites, even with a joint impact, were inferior to β-PhEA-OSAA (their parent compound) by the degree of the total antioxidant activity.
Thus, we have substantiated that the first phase metabolites of the β-phenylethylamide of 2-hydroxysuccinanilic acid biotransformation (2-hydroxyphenyl-succinamide and β-phenylethylsuccinamide) do not exhibit the anti-hyperglycemic activity, but in vitro they possess the antio
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