Sodium-
glucose co-transporter 2 (SGLT2) is predominantly expressed in the S1 segment of the proximal tubule of the kidney and is the major transporter responsible for mediating renal
glucose reabsorption.
Dapagliflozin is an orally active, highly selective
SGLT2 inhibitor that improves
glycemic control in patients with
type 2 diabetes mellitus (T2DM) by reducing renal
glucose reabsorption leading to urinary
glucose excretion (glucuresis). Orally administered
dapagliflozin is rapidly absorbed generally achieving peak plasma concentrations within 2 h. Dose-proportional systemic exposure to
dapagliflozin has been observed over a wide dose range (0.1-500 mg) with an oral bioavailability of 78 %.
Dapagliflozin has extensive extravascular distribution (mean volume of distribution of 118 L).
Dapagliflozin metabolism occurs predominantly in the liver and kidneys by
uridine diphosphate-glucuronosyltransferase-1A9 to the major metabolite
dapagliflozin 3-O-glucuronide (this metabolite is not an
SGLT2 inhibitor at clinically relevant exposures).
Dapagliflozin is not appreciably cleared by renal excretion (<2 % of dose is recovered in urine as parent).
Dapagliflozin 3-O-glucuronide elimination occurs mainly via renal excretion, with 61 % of a
dapagliflozin dose being recovered as this metabolite in urine. The half-life for orally administered
dapagliflozin 10 mg was 12.9 h. Maximal increases in urinary
glucose excretion were seen at doses ≥20 mg/day in patients with T2DM. No clinically relevant differences were observed in
dapagliflozin exposure with respect to age, race, sex,
body weight, food, or presence of T2DM. Pharmacodynamic changes are dependent on plasma
glucose and renal function, and decreases in urinary
glucose excretion were observed due to the lower filtered load (plasma
glucose × glomerular filtration rate) in healthy volunteers compared to subjects with T2DM. After multiple doses of
dapagliflozin, urinary
glucose excretion was associated with dose-related decreases in plasma
glucose parameters in subjects with T2DM. Patients with severe renal or hepatic impairment show higher systemic exposure to
dapagliflozin. No clinically relevant drug interactions were observed that would necessitate dose adjustment of
dapagliflozin when administered with other
antidiabetic or cardiovascular medications, as well as drugs that could potentially influence
dapagliflozin metabolism.