Glipzeal Mechanism of Action

Blood Glucose Lowering Drug (Dipeptidyl Peptidase 4 Inhibitor).
Pharmacology: Pharmacodynamics: Mechanism of action: Sitagliptin phosphate is an orally active, potent, and highly selective inhibitor of the dipeptidyl peptidase 4 (DPP-4) enzyme for the treatment of type 2 diabetes. The DPP-4 inhibitors are a class of agents that act as incretion enhancers. By inhibiting the DPP-4 enzyme, sitagliptin increases the levels of two known active incretion hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase selective inhibitors of the enzyme DPP-4 and do not inhibit the closely related enzymes DPP-8 or DPP-9 at therapeutic concentrations. Sitagliptin differs in chemical structure and pharmacological action from GLP-1 analogs, insulin, sulfonylureas or meglitinides, biguanides, peroxisome proliferator-activated receptor gamma (PPAR) agonists, alpha-glucosidase inhibitors, and amylin analogs. In a two-day study in healthy subjects, sitagliptin alone increases active GLP-1 concentrations, whereas metformin alone increases active and total GLP-1 concentrations to similar extents. Co-administration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations. Sitagliptin, but no metformin, increases active GIP concentrations.
Clinical efficacy and safety Overall: Sitagliptin improved glycemic control when used as monotherapy or in combination treatment in adult patients with type 2 diabetes. In clinical trials, sitagliptin as monotherapy improved glycemic control with significant reductions in hemoglobin A1c (HbA1c) and fasting and post-prandial glucose. Reduction in fasting plasma glucose (FPG) was observed at 3 weeks, the first time point at which FPG was measured. The observed incidence of hypoglycemia in patients treated with sitagliptin was similar to placebo. Body weight did not increase from baseline with sitagliptin therapy. Improvements in surrogate markers of beta cell function, including HOMA-β (Homeostasis Model Assessment-β), proinsulin to insulin ratio, and measures of beta cell responsiveness from the frequently sampled meal tolerance test were observed.
Pharmacokinetics: Absorption: Following oral administration of a 100-mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median T_max) occurring 1 to 4 hours post-dose, the mean plasma AUC of sitagliptin is 8.52 μm/h, C_max is 950 nm. The absolute bioavailability of sitagliptin is approximately 87%. Since co-administration of a high-fat meal with sitagliptin did not affect the pharmacokinetics, it may be administered with or without food. Plasma AUC of sitagliptin increased in a dose-proportional manner. Dose-proportionality was not established for C_max and C_24hr (C_max increased in a greater-than-dose-proportional manner and C_24hr increased in a less-than-dose-proportional manner).
Distribution: The mean volume of distribution at steady state following a single 100-mg intravenous of sitagliptin to healthy subjects is approximately 198 liters. The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).
Biotransformation: Sitagliptin is primarily eliminated unchanged in the urine, and metabolism is a minor pathway. Approximately 79% of sitagliptin is excreted unchanged in the urine. Following a [¹⁴C] sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.
In vitro, data showed that sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19, or 2B6 and is not an inducer of CYP3A4 and CYP1A2.
Elimination: Following administration of an oral [¹⁴C] sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t_1/2 following a 100-mg oral dose of sitagliptin was approximately 12.4 hours. Sitagliptin accumulates only minimally with multiple doses. The renal clearance was approximately 350 mL/min.
Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, ciclosporin, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin. Sitagliptin is not a substrate for OCR2, OAT1, or PEP1/2 transporters. In vitro, sitagliptin did not inhibit OAT3 (IC50=160 μM) or P-glycoprotein (up to 250 μM) mediated transport at therapeutically relevant plasma concentrations. In a clinical study, sitagliptin had a small effect on plasma digoxin concentration indicating that sitagliptin may be a mild inhibitor of p-glycoprotein.
Characteristics in patients: The pharmacokinetics of sitagliptin were generally similar in healthy subjects and in patients with type 2 diabetes.