title: Sustained release of metformin via red blood cell accumulated sulfenamide prodrug.
abstract: Metformin is a first-line antidiabetic drug to treat type 2 diabetes. It is rapidly eliminated from plasma but also accumulated into red blood cells (RBCs) from which it is slowly released back into plasma. The aim of the study was to evaluate whether the amount of metformin in the RBCs could be increased by a sulfenamide prodrug approach, which could provide longer duration of metformin in systemic circulation. Pharmacokinetic properties of metformin and its cyclohexyl sulfenamide prodrug were evaluated in plasma and in whole blood after intravenous and oral administration in rats. Once the sulfenamide prodrug reached the bloodstream, it was rapidly and efficiently accumulated into the RBCs, where it was converted to metformin by free thiols. The RBC-whole blood ratio of metformin was increased approximately from 42% to 96% when metformin was administered intravenously as its sulfenamide prodrug, and the proportion of metformin in the RBCs was found to be concentration and time independent. Because metformin was slowly liberated into plasma, the prodrug showed a sustained-release pharmacokinetic profile and longer plasma half-life for metformin after oral administration. Therefore, this sulfenamide prodrug has great potential to improve metformin therapy as the daily doses could be reduced.
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, KuopioFI-70211, Finland.
authors.forename: Lauri
authors.initials: L
authors.lastname: Peura
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, KuopioFI-70211, Finland. Electronic address: Kristiina.Huttunen@uef.fi.
authors.forename: Kristiina M
authors.initials: KM
authors.lastname: Huttunen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000378:metabolism*; D006207:Half-Life; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood* / Q000737:chemistry; D007275:Injections, Intravenous; D008687:Metformin / Q000008:administration & dosage / Q000097:blood* / Q000737:chemistry; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D013416:Sulfamerazine / Q000008:administration & dosage / Q000097:blood* / Q000737:chemistry; D013997:Time Factors
chemical_list: D003692:Delayed-Action Preparations; D007004:Hypoglycemic Agents; D011355:Prodrugs; C471392:sulfenamide; D008687:Metformin; D013416:Sulfamerazine
keywords: blood flow; controlled release; drug delivery systems; preclinical pharmacokinetics; prodrugs