Dapagliflozin

A Novel Sodium-glucose Cotransporter Type 2 Inhibitor for the Treatment of Type 2 Diabetes Mellitus

Niren K. Shah, Pharm.D.; Wasim E. Deeb, M.D.; Rushab Choksi, Pharm.D.; Benjamin J. Epstein, Pharm.D.

Disclosures

Pharmacotherapy. 2012;32(1):80-94. 

In This Article

Pharmacology and Pharmacokinetics

Dapagliflozin is a potent, highly selective, reversible, and orally active inhibitor of the SGLT2 receptor.[38] 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.[39] 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.[46] It is highly protein bound in plasma (91%) and has limited distribution into human erythrocytes (blood:plasma ratio 0.88).[46] 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.[46] 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.[38] 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.[47]

Renal excretion is a minor elimination pathway for dapagliflozin and its metabolites.[38] 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.[38]

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.

processing....