| Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. | |
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MedLine Citation:
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PMID: 21985634 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Aims: Empagliflozin is a selective sodium glucose cotransporter-2 (SGLT-2) inhibitor in clinical development for the treatment of type 2 diabetes mellitus. This study assessed acute pharmacological properties of empagliflozin in vitro and pharmacokinetic properties in vivo and compared its potency and selectivity with other SGLT-2 inhibitors. Materials and Methods: [(14) C]-alpha-methyl glucopyranoside (AMG) uptake experiments were performed with stable cell lines over-expressing human (h) SGLT-1, 2 and 4. Two new cell lines over-expressing hSGLT-5 and hSGLT-6 were established and [(14) C]-mannose and [(14) C]-myo-inositol uptake assays developed. Binding kinetics were analyzed using a radioligand binding assay with [(3) H]-labelled empagliflozin and HEK293-hSGLT-2 cell membranes. Acute in vivo assessment of pharmacokinetics was performed with normoglycaemic beagle dogs and Zucker Diabetic Fatty (ZDF) rats. Results: Empagliflozin has an IC(50) of 3.1 nM for hSGLT-2. Its binding to SGLT-2 is competitive with glucose (half-life approximately 1 hour). Compared with other SGLT-2 inhibitors, empagliflozin has a high degree of selectivity over SGLT-1, 4, 5 and 6. Species differences in SGLT-1 selectivity were identified. Empagliflozin pharmacokinetics in ZDF rats were characterized by moderate total plasma clearance (CL) and bioavailability (BA), while in beagle dogs CL was low and BA was high. Conclusions: Empagliflozin is a potent and competitive SGLT-2 inhibitor with an excellent selectivity profile and the highest selectivity window of the tested SGLT-2 inhibitors over hSGLT-1. Empagliflozin represents an innovative therapeutic approach to treat diabetes. |
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Authors:
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Rolf Grempler; Leo Thomas; Matthias Eckhardt; Frank Himmelsbach; Achim Sauer; Dale E Sharp; Remko A Bakker; Michael Mark; Thomas Klein; Peter Eickelmann |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-10-10 |
Journal Detail:
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Title: Diabetes, obesity & metabolism Volume: - ISSN: 1463-1326 ISO Abbreviation: - Publication Date: 2011 Oct |
Date Detail:
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Created Date: 2011-10-11 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100883645 Medline TA: Diabetes Obes Metab Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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© 2011 Blackwell Publishing Ltd. |
Affiliation:
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CardioMetabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co.KG, Biberach, Germany Medicinal Chemistry, Boehringer Ingelheim Pharma GmbH & Co.KG, Biberach, Germany Drug Discovery Support, Boehringer Ingelheim Pharma GmbH & Co.KG, Biberach, Germany Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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