Tenelizone Mechanism of Action

Pharmacology: Pharmacodynamics: Teneligliptin is a novel highly selective DPP-4 (dipeptidyl peptidase-4) inhibitor. It shows a unique chemical structure which is characterized by five consecutive rings (J-shaped), thereby potentially producing unique characteristics including its glucose lowering efficacy and half-life. Incretin hormones, namely glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released from enteroendocrine cells and enhance insulin secretion. Incretins are rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4), and as a result have a very short half-life (t_1/2). DPP-4 inhibitors increase the levels of active GLP-1 and GIP by inhibiting DPP-4 enzymatic activity; thus, in patients with diabetes, these inhibitors improve hyperglycemia in a glucose-dependent manner by increasing serum insulin levels and decreasing serum glucagon levels. Glycemic efficacy of Teneligliptin is obtained through activating beta-cell function as well as decreasing insulin resistance.
Pioglitazone effects may be mediated by a reduction of insulin resistance. Pioglitazone appears to act via activation of specific nuclear receptors (peroxisome proliferator activated receptor gamma) leading to increased insulin sensitivity of liver, fat and skeletal muscle cells in animals. Treatment with Pioglitazone has been shown to reduce hepatic glucose output and to increase peripheral glucose disposal in the case of insulin resistance.
Fasting and postprandial glycemic control is improved in patients with type 2 diabetes mellitus. The improved glycemic control is associated with a reduction in both fasting and postprandial plasma insulin concentrations.
Pharmacokinetics: The plasma concentrations of Teneligliptin after the administration of Teneligliptin at dosages of 10 or 20 mg once daily for 4 weeks revealed a median time to maximum concentration (C_max) of 1.0 hour in both groups and a mean half-life of 20.8 and 18.9 hours, respectively. The AUC_0-2h values for the active GLP-1 concentration after breakfast, lunch, and dinner were 8.0, 8.4, and 7.8 pmol•h/L, respectively, in the 10 mg Teneligliptin group, and 8.3, 7.9, and 8.6 pmol•h/L, respectively, in the 20 mg Teneligliptin group. About 34.4% of Teneligliptin is excreted unchanged via the kidney and the remaining 65.6% Teneligliptin is metabolized and eliminated via renal and hepatic excretion. Following oral administration, Pioglitazone is rapidly absorbed, and peak plasma concentrations of unchanged Pioglitazone are usually achieved 2 hours after administration. Proportional increases of the plasma concentration were observed for doses from 2-60 mg. Steady state is achieved after 4-7 days of dosing. Repeated dosing does not result in accumulation of the compound or metabolites. Absorption is not influenced by food intake. Absolute bioavailability is greater than 80%. The estimated volume of distribution in humans is 0.25 L/kg. Pioglitazone and all active metabolites are extensively bound to plasma protein (> 99%). Pioglitazone undergoes extensive hepatic metabolism by hydroxylation of aliphatic methylene groups. Following oral administration of radio labelled Pioglitazone to man, recovered label was mainly in feces (55%) and a lesser amount in urine (45%). The mean plasma elimination half-life of unchanged Pioglitazone in man is 5 to 6 hours and for its total active metabolites 16 to 23 hours.