Pharmacology and Pharmacokinetics
Dapagliflozin is a potent, highly selective, reversible, and orally active inhibitor of the SGLT2 receptor. Based on in vitro studies, dapagliflozin exhibits a mean inhibitory potential (EC50) of 1.12 nmol/L against human SGLT2 and an EC50 of 1391.00 nmol/L against human SGLT1, representing a highly selective profile for SGLT2 versus SGLT1 (~1200-fold).[39,40] Dapagliflozin minimally inhibits the facilitative glucose transporters GLUT1 and GLUT2, and modestly inhibits GLUT4.
As a result of this mechanism profile, dapagliflozin produces dose-dependent and sustained plasma glucose lowering by promoting urinary glucose excretion. A reduction in both fasting and postprandial glucose concentrations results in the consumption of fat as an energy source.[41–43] Chronic SGLT2 inhibition with dapagliflozin results in reduced hepatic glucose production, increased insulin sensitivity, enhanced glucose influx into the liver, and improvements in islet morphology without reductions in β-cell mass, although these mechanisms have not been fully elucidated. Dapagliflozin also shows dose-dependent decreases in body weight, proposed to be secondary to caloric loss as a result of glucosuria and an osmotic-diuretic effect.[44,45]
Table 1 lists the pharmacokinetic parameters of dapagliflozin. Dapagliflozin demonstrates linear pharmacokinetics and is rapidly absorbed after oral administration. It is highly protein bound in plasma (91%) and has limited distribution into human erythrocytes (blood:plasma ratio 0.88). Because of its C-glucoside chemical structure, dapagliflozin is metabolically stable and exhibits a long half-life (13.8 ± 9.4 hrs), allowing for once-daily dosing. Dapagliflozin is predominantly metabolized by uridine diphosphate–glucuronosyltransferase 1A9 into non–pharmacologically active glucuronides in human hepatocytes.[38,46] In vitro studies have identified an O-deethylated active metabolite (BMS-511926) of dapagliflozin, which has similar SGLT2 inhibitory values as dapagliflozin. However, BMS-511926 is only present with dapagliflozin doses greater than 50 mg secondary to its low area under the concentration-time curve (AUC).
There were no relevant interactions noted between dapagliflozin and substrates of cytochrome P450 (CYP) isoenzymes and P-glycoprotein (P-gp), or due to plasma protein binding.[38,46] It is expected that drugs interacting with CYP isoenzymes or P-gp transporters will not interfere with dapagliflozin activity, and no dosage adjustment of either drug will be necessary. A recent study showed that coadministration of dapagliflozin with pioglitazone, metformin, glimepiride, or sitagliptin did not affect AUC or the maximum plasma concentrations of either drug.
Renal excretion is a minor elimination pathway for dapagliflozin and its metabolites. In healthy subjects, food has only a modest effect on the pharmacokinetic profile of dapagliflozin. A high-fat meal did not produce meaningful changes in urinary glucose excretion.
Pharmacotherapy. 2012;32(1):80-94. © 2012 Pharmacotherapy Publications