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Multiple‐Dose Pharmacokinetics and Pharmacodynamics of Sergliflozin Etabonate, a Novel Inhibitor of Glucose Reabsorption, in Healthy Overweight and Obese Subjects: A Randomized Double‐Blind Study
Author(s) -
Hussey Elizabeth K.,
Dobbins Robert L.,
Stoltz Randall R.,
Stockman Nancy L.,
O'ConnorSemmes Robin L.,
Kapur Anita,
Murray Sharon C.,
Layko Debbi,
Nunez Derek J. R.
Publication year - 2010
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270009352185
Subject(s) - pharmacokinetics , pharmacodynamics , medicine , placebo , renal function , pharmacology , renal glucose reabsorption , endocrinology , diabetes mellitus , type 2 diabetes , alternative medicine , pathology
Sergliflozin, the active entity of sergliflozin etabonate, is a selective inhibitor of the sodium‐dependent glucose cotransporter‐2 in the renal tubule. The pharmacokinetics and pharmacodynamics of sergliflozin were examined during administration of sergliflozin etabonate (500 or 1000 mg) or placebo 3 times daily (tid) for 14 days in healthy overweight or obese human volunteers (n = 18). At the doses tested, sergliflozin showed less than dose‐proportional pharmacokinetic characteristics. Mean half‐life of the active entity was approximately 2 hours; there was no evidence of drug accumulation. Sergliflozin etabonate produced rapid and sustained suppression of renal glucose reabsorption, resulting in a dose‐related glucosuria, and a transient increase in urinary electrolyte and fluid loss; plasma glucose, insulin, and electrolyte levels were unchanged. Sergliflozin etabonate produced a rapid, dose‐related reduction in body weight (mean changes of −0.09, −1.55, and −1.74 kg from baseline to day 15 with placebo, sergliflozin etabonate 500 mg, and sergliflozin etabonate 1000 mg, respectively), apparently through increased urinary calorie loss rather than through osmotic diuresis. Sergliflozin etabonate 500 or 1000 mg tid was generally well tolerated; no clinically significant adverse events were identified. Renal function (creatinine clearance) was not affected by sergliflozin etabonate, although urinary microalbumin, N‐acetyl‐beta‐D‐glucosaminidase, and β 2 ‐microglobulin levels tended to increase.