Glyhart Mechanism of Action

Pharmacology: Pharmacodynamics: Dapagliflozin is a potent, reversible and highly selective inhibitor of sodium-glucose co-transporter 2 (SGLT2), a transporter that is expressed in the proximal renal tubules and is responsible for most of the reabsorption of filtered glucose from the tubular lumen. Through inhibition of SGLT2, dapagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose in a dose-dependent manner, leading to increased urinary glucose excretion; increased glucose excretion is independent of insulin secretion.
Dapagliflozin also reduces sodium reabsorption and increases sodium delivery to the distal tubule. This may influence several physiologic functions including lowering cardiac preload and afterload and downregulation of sympathetic activity.
Pharmacokinetics: Dapagliflozin is rapidly absorbed after oral administration with maximum plasma concentration (C_max) occurring within 2 hours under fasting state. The C_max and area under the concentration-time curve (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 time to peak plasma concentration (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 significant. Dapagliflozin may be administered with or without food.
Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment. The mean steady-state volume of distribution of dapagliflozin is 118 L.
Dapagliflozin is extensively metabolized, primarily to yield dapagliflozin 3-O-glucuronide, an inactive metabolite, via uridine diphosphate-glucuronosyltransferase (UGT) isoenzyme 1A9 in the liver and kidney.
Dapagliflozin and related metabolites are mainly eliminated via the renal pathway. After the administration of a single 50 mg radiolabeled dose of dapagliflozin, 75% and 21% total radioactivity is excreted in urine and feces, respectively, with less than 2% in urine as parent drug and approximately 15% in feces as parent drug. The mean terminal elimination half-life of dapagliflozin is approximately 12.9 hours.
Special Populations: Renal Impairment: Patients with type 2 diabetes mellitus and mild, moderate, or severe renal impairment had mean systemic exposures of dapagliflozin that were 32%, 60% and 87% higher, respectively, compared to patients with type 2 diabetes mellitus and normal renal function.
Hepatic Impairment: In patients with mild or moderate hepatic impairment (Child-Pugh classes A and B), mean C_max and AUC of dapagliflozin were up to 12% and 36% higher, respectively, compared with normal subjects. In patients with severe impairment (Child-Pugh class C), mean C_max and AUC of dapagliflozin were increased up to 40% and 67%, respectively.
Elderly: There is no clinically significant increase in exposure based on age alone in subjects up to 70 years old. However, an increased exposure due to age-related decrease in renal function can be expected.