Dapazin Mechanism of Action

Pharmacotherapeutic group: Drugs used in diabetes, Blood Glucose Lowering Drugs, Excl. Insulins-Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitors. ATC code: A10BK01.
Pharmacology: Pharmacodynamics: Mechanism of Action: Sodium-Glucose Co-Transporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Dapagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, Dapagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion. Dapagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This may influence several physiological functions including, but not restricted to, lowering both pre- and afterload of the heart and down regulation of sympathetic activity.
General: Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in patients with type 2 diabetes mellitus following the administration of Dapagliflozin. Dapagliflozin doses of 5 or 10 mg per day in patients with type 2 diabetes mellitus for 12 weeks resulted in excretion of approximately 70 grams of glucose in the urine per day at week 12. A near maximum glucose excretion was observed at the Dapagliflozin daily dose of 20 mg. This urinary glucose excretion with Dapagliflozin also results in increases in urinary volume. After discontinuation of Dapagliflozin, on average, the elevation in urinary glucose excretion approaches baseline by about 3 days for the 10 mg dose.
Pharmacokinetics: Absorption: Following oral administration of Dapagliflozin, the maximum plasma concentration (C_max) is usually attained within 2 hours under fasting state. The C_max and AUC values increase dose proportionally with increase in Dapagliflozin dose in the therapeutic dose range. The absolute oral bioavailability of Dapagliflozin following the administration of a 10 mg dose is 78%. Administration of Dapagliflozin with a high-fat meal decreases its C_max by up to 50% and prolongs T_max by approximately 1 hour, but does not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful and Dapagliflozin can be administered with or without food.
Distribution: Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment.
Metabolism: The metabolism of Dapagliflozin is primarily mediated by UGT1A9; CYP-mediated metabolism is a minor clearance pathway in humans. Dapagliflozin is extensively metabolized, primarily to yield Dapagliflozin 3-o-glucuronide, which is an inactive metabolite. Dapagliflozin 3-o-glucuronide accounted for 61% of a 50 mg [¹⁴C]-Dapagliflozin dose and is the predominant drug-related component in human plasma.
Elimination: Dapagliflozin and related metabolites are primarily eliminated via the renal pathway. Following a single 50 mg dose of [¹⁴C]-Dapagliflozin, 75% and 21% total radioactivity is excreted in urine and feces, respectively. In urine, less than 2% of the dose is excreted as parent drug. In feces, approximately 15% of the dose is excreted as parent drug. The mean plasma terminal half-life (t½) for Dapagliflozin is approximately 12.9 hours following a single oral dose of Dapagliflozin 10 mg.