title: Pharmacogenetic variation and metformin response.
abstract: Diabetes is a major health problem worldwide, and metformin, a traditional oral anti-hyperglycemic drug, is now believed to be the most widely prescribed antidiabetic drug. Metformin acts primarily by inhibiting hepatic glucose production and improving insulin sensitivity. Metformin is absorbed predominately by the small intestine and excreted in an unaltered form in the urine. The pharmacokinetics of metformin is primarily determined by membrane transporters, including the plasma membrane monoamine transporter (PMAT), the organic cation transporters (OCTs), the multidrug and toxin extrusion (MATE) transporters, and the critical protein kinase AMPactivated protein kinase (AMPK). PMAT may play a role in the uptake of metformin from the gastrointestinal tract, while OCTs mediate the intestinal absorption, hepatic uptake, and renal excretion of metformin. MATEs are believed to contribute to the hepatic and renal excretion of the drug. The pharmacologic effects of metformin are primarily exerted in the liver, at least partly via the activation of AMPK and the subsequent inhibition of gluconeogenesis. A considerable amount of pharmacogenetic research has demonstrated that genetic variation is one of the major factors affecting metformin response. Moreover, it has become increasingly clear that membrane transporters are important determinants of the pharmacokinetics of metformin. In this review, we will discuss the genetic variants of major transporters that purportedly determine the pharmacokinetics of metformin in terms of drug bioavailability, distribution, and excretion, such as PMAT, OCTs, and MATEs. Understanding how genetic variation affects metformin response will help promote more effective use of the drug for the treatment of type 2 diabetes (T2D).
authors: Suning
authors: S
authors: Chen
authors: Jie
authors: J
authors: Zhou
authors: Miaomiao
authors: M
authors: Xi
authors: Yanyan
authors: Y
authors: Jia
authors: Yan
authors: Y
authors: Wong
authors: Jinyi
authors: J
authors: Zhao
authors: Likun
authors: L
authors: Ding
authors: Jian
authors: J
authors: Zhang
authors: Department of Pharmacy, Xijing Hospital, and The State Key Laboratory of Cancer Biology and The Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi Province, 710032, People's Republic of China. adwen_2004@hotmail.com.
authors: Aidong
authors: A
authors: Wen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001682:Biological Availability; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D014644:Genetic Variation; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008657:Metabolic Clearance Rate; D008687:Metformin / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009132:Muscles / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D010597:Pharmacogenetics / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D007004:Hypoglycemic Agents; D027701:Organic Cation Transport Proteins; D020033:Protein Isoforms; D008687:Metformin; D055372:AMP-Activated Protein Kinases