title: Genetic Polymorphisms in Organic Cation Transporter 1 Attenuates Hepatic Metformin Exposure in Humans.
abstract: Metformin has been used successfully to treat type 2 diabetes for decades. However, the efficacy of the drug varies considerably from patient to patient and this may in part be due to its pharmacokinetic properties. The aim of this study was to examine if common polymorphisms in SLC22A1, encoding the transporter protein OCT1, affect the hepatic distribution of metformin in humans. We performed noninvasive11C-metformin positron emission tomography (PET)/computed tomography (CT) to determine hepatic exposure in 12 subjects genotyped for variants in SLC22A1. Hepatic distribution of metformin was significantly reduced after oral intake in carriers of M420del and R61C variants in SLC22A1 without being associated with changes in circulating levels of metformin. Our data show that genetic polymorphisms in transporter proteins cause variation in hepatic exposure to metformin, and it demonstrates the application of novel imaging techniques to investigate pharmacogenetic properties in humans.
authors.affiliation: Research Laboratory for Biochemical Pathology, Department of Clinical Medicine, Aarhus University Hospital, Denmark.
authors.forename: Eio
authors.initials: E
authors.lastname: Sundelin
authors.affiliation: Department of Nuclear Medicine and PET Center, Aarhus University Hospital, Denmark.
authors.forename: L C
authors.initials: LC
authors.lastname: Gormsen
authors.affiliation: Research Laboratory for Biochemical Pathology, Department of Clinical Medicine, Aarhus University Hospital, Denmark.|Department of Nuclear Medicine and PET Center, Aarhus University Hospital, Denmark.
authors.forename: J B
authors.initials: JB
authors.lastname: Jensen
authors.affiliation: Department of Nuclear Medicine and PET Center, Aarhus University Hospital, Denmark.
authors.forename: M H
authors.initials: MH
authors.lastname: Vendelbo
authors.affiliation: Department of Nuclear Medicine and PET Center, Aarhus University Hospital, Denmark.
authors.forename: S
authors.initials: S
authors.lastname: Jakobsen
authors.affiliation: Department of Nuclear Medicine and PET Center, Aarhus University Hospital, Denmark.
authors.forename: O L
authors.initials: OL
authors.lastname: Munk
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Denmark.
authors.forename: Mmh
authors.initials: M
authors.lastname: Christensen
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Denmark.|Department of Public Health, Clinical Pharmacology, University of Southern Denmark, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Brøsen
authors.affiliation: Department of Nuclear Medicine and PET Center, Aarhus University Hospital, Denmark.
authors.forename: J
authors.initials: J
authors.lastname: Frøkiaer
authors.affiliation: Research Laboratory for Biochemical Pathology, Department of Clinical Medicine, Aarhus University Hospital, Denmark.|Department of Clinical Pharmacology, Aarhus University Hospital, Denmark.
authors.forename: N
authors.initials: N
authors.lastname: Jessen
mesh_terms: D000328:Adult; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000378:metabolism; D007275:Injections, Intravenous; D008099:Liver / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000008:administration & dosage* / Q000378:metabolism; D008875:Middle Aged; D050811:Octamer Transcription Factor-1 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D049268:Positron-Emission Tomography / Q000379:methods
chemical_list: D007004:Hypoglycemic Agents; D050811:Octamer Transcription Factor-1; C494165:POU2F1 protein, human; D008687:Metformin