Sitagliptin In Rats Research Articles

Chemistry and Hypoglycemic Activity of GPR119 Agonist ZB-16

This article is to highlight the chemical properties and primary pharmacology of novel GPR119 agonist ZB-16 and its analogs, which were rejected during the screening. Experiments were performed in vitro (specific activity, metabolism and cell toxicity) and in vivo (hypoglycemic activity and pharmacokinetics). ZB-16 exhibits nanomolar activity (EC50 = 7.3–9.7 nM) on target receptor GPR119 in vitro associated with hypoglycemic activity in vivo. In animals with streptozotocin-nicotinamide induced type 2 diabetes mellitus (STZ-NA T2D) daily oral dose of ZB-16 (1 mg/kg) or sitagliptin (10 mg/kg) for 28 days resulted in the reduction of blood glucose levels. The effects of ZB-16 were comparable to the hypoglycemic action of sitagliptin. ZB-16 demonstrated relatively low plasma exposition, high distribution volume, mild clearance and a prolonged half-life (more than 12 h). The present study demonstrates that the targeted search for selective GPR119 receptor agonists is a well-founded approach for developing novel drugs for the therapy of T2D. Based on the combination of high in vitro activity (compared to competitor standards), a useful ADME profile, distinct hypoglycemic activity which is comparable to the efficacy of sitagliptin in rats with experimental T2D, and the acceptable pharmacokinetic profile, we recommend the ZB-16 compound for further research.

Microwave Assisted Acrylamide Grafting on a Natural Gum Cassia Tora: Characterization and Pharmacokinetic Evaluation of the Formulation Containing Metformin and Sitagliptin in Rats by LC-MS/MS

A vast proportion of synthesis based polymers used to develop matrix drug delivery systems are too some extent harmful to patients who are taking those formulations for shorter and longer duration of time. Long term toxic effect of synthetic polymers can be countered by replacing those with substituted natural polymers. Under influence of microwave dielectric heating natural gums can be modified as promising biodegradable polymeric materials. The grafting as a tool to manipulate natural polysaccharides with the precise control over the features of the grafted polymer, under microwave irradiation can be a powerful strategy for the development of natural polymers with tailor made properties. The grafting of acrylamide onto cassia tora (CT) was carried out using microwave-assisted graft copolymerization and was characterized. The acute oral toxicity study in rodents was carried out according to OECD guideline. The pharmaceutical application in the tablet formulation of the acrylamide grafted CT (best batch) was studied by using metformin and sitagliptin as model drugs. It can be concluded that microwave assisted acrylamide grafting on cassia tora was successful. The developed formulation with the grafted CT as polymer was also studied in rats for pharmacokinetic profiling. The developed bioanalytical method to determine both the drugs in rat plasma was found simple, reproducible and validated as per the guidelines.

Determination of Sitagliptin Levels in Rats Serum by HPLC and its Pharmacokinetic Investigation in Existence of Sucralose

It is an interest of the current work to develop a simple, valid and rapid chromatographic method for the quantification of sitagliptin in rats' serum. Accordingly, the pharmacokinetic parameters of sitagliptin was investigated for any possible interaction between sitagliptin and sucralose. The developed HPLC method was validated for sitagliptin determination in rat’s serum. Results indicated an accomplished overall intra-day precision and accuracy values of 0.139-4.028 (CV%) and 99.48-107.12% respectively. On the other hand, inter-day precision and accuracy results recorded values of 0.150-2.810 (CV%) and 99.90-116.00% respectively. Moreover, the coefficient of correlation was determined at a value of 0.99950 with reasonable sensitivity and selectivity. Effect of sucralose showed strong significant correlation on sitagliptin serum profile. The precise, accurate, linear, sensitive and selective HPLC method will be elaborated in the context of the current work with emphasis on sucralose negative effect on sitagliptin level in rat’s serum. Such finding is a guidance for physicians to reconsider the use of such sweeteners for diabetic patients

Comparing hypoglycemic activity of novel GPR119 agonist and DPP-4 inhibitor sitagliptin

Hypoglycemic drugs affecting the incretin system increasingly becoming popular because of its high safety and efficacy. The regulation of the secretion of endogenous incretin involves a number of receptors on the enteroendocrine cells, among which the most promising is GPR119. After activation it increases the incretins secretion and glucose-dependent insulin secretion, that is important from the point of view of effective control of postprandial glucose levels with minimal risk of hypoglycemia.Aims.To conduct a comparative study of hypoglycemic activity of DPP-4 inhibitors (sitagliptin) and novel GPR119 agonist receptor — compound ZB-16 in streptozotocin-nicotinamide-induced rat model of type 2 diabetes mellitus (T2DM).Material and methods.The hypoglycemic effect of ZB-16 (0.1 and 1 mg/kg per os) and sitagliptin (10 mg/kg per os) was studied during 4-week administration in 50 adult female rats (6 months, 240—260 g) with streptozotocin-nicotinamide-induced T2DM. The oral glucose tolerance test (OGTT) was performed on the 14th and 28th day after the start of treatment.Results.Animals receiving compound ZB-16 at a dose of 1 mg/kg by the end of treatment there have a significant reduction in fasting glucose as compared with the control group (7.9±0.43 and 0.54±9,6 mmol/l, respectively). During the OGTT on day 28 of treatment compound ZB-16 improves the rate of glucose utilization, reducing «peak» of growth glycemia (15,7±0,88 versus 21,6±1,06 mmol/L) and area under the curve «glucose concentration-time» (to 25%) compared with the control group during the OGTT.Conclusions.Novel GPR119 agonist — ZB-16 (1 mg/kg) has a clear hypoglycemic effect comparable to that of sitagliptin in rats with streptozotocin-nicotinamide-induced T2DM.

Disposition of the Dipeptidyl Peptidase 4 Inhibitor Sitagliptin in Rats and Dogs

The pharmacokinetics, metabolism, and excretion of sitagliptin [MK-0431; (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine], a potent dipeptidyl peptidase 4 inhibitor, were evaluated in male Sprague-Dawley rats and beagle dogs. The plasma clearance and volume of distribution of sitagliptin were higher in rats (40-48 ml/min/kg, 7-9 l/kg) than in dogs ( approximately 9 ml/min/kg, approximately 3 l/kg), and its half-life was shorter in rats, approximately 2 h compared with approximately 4 h in dogs. Sitagliptin was absorbed rapidly after oral administration of a solution of the phosphate salt. The absolute oral bioavailability was high, and the pharmacokinetics were fairly dose-proportional. After administration of [(14)C]sitagliptin, parent drug was the major radioactive component in rat and dog plasma, urine, bile, and feces. Sitagliptin was eliminated primarily by renal excretion of parent drug; biliary excretion was an important pathway in rats, whereas metabolism was minimal in both species in vitro and in vivo. Approximately 10 to 16% of the radiolabeled dose was recovered in the rat and dog excreta as phase I and II metabolites, which were formed by N-sulfation, N-carbamoyl glucuronidation, hydroxylation of the triazolopiperazine ring, and oxidative desaturation of the piperazine ring followed by cyclization via the primary amine. The renal clearance of unbound drug in rats, 32 to 39 ml/min/kg, far exceeded the glomerular filtration rate, indicative of active renal elimination of parent drug.