Dapagliflozin inhibits subtype 2 of the sodium-glucose transport proteins (SGLT2) which are responsible for at least 90% of the glucose re-absorption in the kidney. Blocking this transporter mechanism causes blood glucose to be eliminated through the urine.
Metformin lowers both basal and PPG. It works mainly by suppressing excessive hepatic glucose production, through a reduction in gluconeogenesis . Other potential effects of metformin include an increase in glucose uptake, an increase in insulin signaling, a decrease in fatty acid and triglyceride synthesis, and an increase in fatty acid β-oxidation. Metformin may also increase glucose utilization in peripheral tissues, and possibly reduce food intake and intestinal glucose absorption.
As metformin does not stimulate endogenous insulin secretion, it does not cause hypoglycemia or hyperinsulinemia, which are common side effects associated with other antidiabetic drugs.
Following oral administration of dapagliflozin, the maximum plasma concentration (Cmax) is usually attained within 2 hours under fasting state. The Cmax 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 Cmax by up to 50% and prolongs Tmax 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.
Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment.
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.
EliminationDapagliflozin 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
Metformin is not metabolized and is excreted unchanged in the urine, with a half-life of ~5 h.
The population mean for renal clearance (CLr) is 510±120 ml/min. Active tubular secretion in the kidney is the principal route of metformin elimination
The drug is widely distributed into body tissues including the intestine, liver, and kidney by organic cation transporters .
Dapaveldactin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus