title: Drug interactions with oral antidiabetic agents: pharmacokinetic mechanisms and clinical implications.
abstract: There is a growing epidemic of type 2 diabetes (T2DM), and it is associated with various comorbidities. Patients with T2DM are usually treated with multiple drugs, and are therefore at an increased risk of harmful drug-drug interactions (DDIs). Several potentially life-threatening DDIs concerning oral antidiabetic drugs have been identified. This has mostly been initiated by case reports but, more recently, the understanding of their mechanisms has greatly increased. In this article, we review the pharmacokinetic DDIs concerning oral antidiabetics, including metformin, sulfonylureas, meglitinide analogs, thiazolidinediones and dipeptidyl peptidase-4 inhibitors, and the underlying mechanistic basis that can help to predict and prevent DDIs. In particular, the roles of membrane transporters and cytochrome P450 (CYP) enzymes in these DDIs are discussed.
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Tukholmankatu 8C, FIN-00290 Helsinki, Finland.
authors.forename: Aleksi
authors.initials: A
authors.lastname: Tornio
authors.forename: Mikko
authors.initials: M
authors.lastname: Niemi
authors.forename: Pertti J
authors.initials: PJ
authors.lastname: Neuvonen
authors.forename: Janne T
authors.initials: JT
authors.lastname: Backman
mesh_terms: D000284:Administration, Oral; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors; D001549:Benzamides / Q000008:administration & dosage / Q000493:pharmacokinetics; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D065607:Cytochrome P-450 Enzyme Inhibitors; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D004347:Drug Interactions; D006801:Humans; D007003:Hypoglycemia / Q000150:complications*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008687:Metformin / Q000008:administration & dosage / Q000493:pharmacokinetics; D013453:Sulfonylurea Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D001549:Benzamides; D065607:Cytochrome P-450 Enzyme Inhibitors; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones; C030516:meglitinide; D008687:Metformin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8