title: A comparison of uptake of metformin and phenformin mediated by hOCT1 in human hepatocytes.
abstract: Metformin, a biguanide that has been used to treat type 2 diabetes mellitus, is reportedly transported into human hepatocytes by human organic cation transporter 1 (hOCT1). The objective of this study was to investigate differences in the hepatic uptake of metformin and phenformin, a biguanide derivative similar to metformin. Special focus was on the role of active transport into cells. Experiments were therefore performed using human cryopreserved hepatocytes and hOCT1 expressing oocytes. Both biguanides proved to be good substrates for hOCT1. However, phenformin exhibited a much higher affinity and transport activity, with a marked difference in uptake kinetics compared with metformin. Both biguanides were transported actively by hOCT1, with the active transport components much greater than passive transport components in both cases, suggesting that functional changes in hOCT1 might affect the transport of both compounds to the same degree. This study for the first time produced detailed comparative findings for uptake profiles of metformin and phenformin in human hepatocytes and hOCT1 expressing oocytes. It is considered that hOCT1 may not be the only key factor that determines the frequency of metformin and phenformin toxicity, considering the major contribution of this transporter to the total hepatic uptake and comparable width of their therapeutic concentrations.
authors.affiliation: Pharmacokinetics Research Laboratories, Dainippon Sumitomo Pharma Co. Ltd, 1-98 Kasugade-naka 3-chome, Konohana-ku, Osaka, 554-0022, Japan. yoshihisa-sogame@ds-pharma.co.jp
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Sogame
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kitamura
authors.forename: Masashi
authors.initials: M
authors.lastname: Yabuki
authors.forename: Setsuko
authors.initials: S
authors.lastname: Komuro
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects; D008687:Metformin / Q000494:pharmacology*; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D027702:Organic Cation Transporter 1 / Q000378:metabolism*; D010629:Phenformin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001647:Bile Acids and Salts; D007004:Hypoglycemic Agents; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D008687:Metformin; D010629:Phenformin; D000410:Alanine Transaminase