Clinical pharmacokinetics and pharmacodynamics of dapagliflozin, a selective inhibitor of sodium-glucose co-transporter type 2.
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Kasichayanula S, Liu X, Lacreta F, Griffen SC, Boulton DW
Clinical pharmacokinetics and pharmacodynamics of dapagliflozin, a selective inhibitor of sodium-glucose co-transporter type 2.
Clin Pharmacokinet. 2014 Jan;53(1):17-27. doi: 10.1007/s40262-013-0104-3.
- PubMed ID
- 24105299 [ View in PubMed]
- Abstract
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 x 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.
DrugBank Data that Cites this Article
- Drugs
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Dapagliflozin Cytochrome P450 1A1 Protein Humans NoSubstrateDetails Dapagliflozin Cytochrome P450 1A2 Protein Humans NoSubstrateDetails Dapagliflozin Cytochrome P450 2A6 Protein Humans NoSubstrateDetails Dapagliflozin Cytochrome P450 2C9 Protein Humans NoSubstrateDetails Dapagliflozin Cytochrome P450 2D6 Protein Humans NoSubstrateDetails Dapagliflozin Cytochrome P450 3A4 Protein Humans NoSubstrateDetails Dapagliflozin UDP-glucuronosyltransferase 1-9 Protein Humans NoSubstrateDetails Dapagliflozin UDP-glucuronosyltransferase 2B4 Protein Humans NoSubstrateDetails Dapagliflozin UDP-glucuronosyltransferase 2B7 Protein Humans NoSubstrateDetails - Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Dapagliflozin P-glycoprotein 1 Protein Humans UnknownSubstrateDetails