title: The first bioreversible prodrug of metformin with improved lipophilicity and enhanced intestinal absorption.
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.
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kuopio, FI-70211 Kuopio, Finland. Kristiina.Huttunen@uku.fi
authors.forename: Kristiina M
authors.initials: KM
authors.lastname: Huttunen
authors.forename: Anne
authors.initials: A
authors.lastname: Mannila
authors.forename: Krista
authors.initials: K
authors.lastname: Laine
authors.forename: Eeva
authors.initials: E
authors.lastname: Kemppainen
authors.forename: Jukka
authors.initials: J
authors.lastname: Leppänen
authors.forename: Jouko
authors.initials: J
authors.lastname: Vepsäläinen
authors.forename: Tomi
authors.initials: T
authors.lastname: Järvinen
authors.forename: Jarkko
authors.initials: J
authors.lastname: Rautio
mesh_terms: D000818:Animals; D001682:Biological Availability; D002021:Buffers; D015195:Drug Design; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D007408:Intestinal Absorption; D008297:Male; D008687:Metformin / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics; D000442:Octanols / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D012996:Solutions; D013416:Sulfamerazine / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D002021:Buffers; D000442:Octanols; D011355:Prodrugs; D012996:Solutions; C471392:sulfenamide; D014867:Water; D008687:Metformin; D006861:Hydrogen Peroxide; D013416:Sulfamerazine