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An In Ovo Model for Testing Insulin-mimetic Compounds
Published on: April 23, 2018
The first bioreversible prodrug of metformin with improved lipophilicity and enhanced intestinal absorption
Kristiina M Huttunen1, Anne Mannila, Krista Laine
1Department of Pharmaceutical Chemistry, University of Kuopio, FI-70211 Kuopio, Finland. Kristiina.Huttunen@uku.fi
Abstract:
Metformin is a potent antidiabetic agent and currently used as a first-line treatment for patients with type 2 diabetes. Unfortunately, the moderate absorption and uncomfortable gastrointestinal adverse effects associated with metformin therapy impair its use. In this study, two novel prodrugs of a biguanidine functionality containing antidiabetic agent, metformin, were designed, synthesized, and evaluated in vitro and in vivo to accomplish improved lipophilicity and, consequently, enhanced oral absorption of this highly water-soluble drug. These results represent that the more lipophilic prodrug 2a biotransformed quantitatively to metformin mainly after absorption. The enhanced oral absorption consequently promoted the bioavailability of metformin from 43% to 65% in rats. Thus, this novel prodrug may offer a solution to reduce the required daily doses of metformin, which may decrease the uncomfortable adverse effects associated with metformin therapy.
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