Evidence map›Paper›PMID 25920679›Full record

ArticleMolecular pharmacology2015

Targeted disruption of organic cation transporter 3 attenuates the pharmacologic response to metformin.

Eugene C Chen, Xiaomin Liang, Sook Wah Yee, Ethan G Geier, Sophie L Stocker, Ligong Chen, Kathleen M Giacomini

Registry-linked trialOpen access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular pharmacology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT04448821 (A Clinical Trial to Evaluate the Effect of Nilotinib on the Pharmacokinetics and Pharmacodynamics of Metformin in Healthy Male Adults), which is not on this map. Cited by 65 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
65citing papers in PubMed, 2 pooled it
4.6field-weighted citation impact, top 4% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT04448821 phase1completednot on this mapstarted 2020, after this paper: background citation

A Clinical Trial to Evaluate the Effect of Nilotinib on the Pharmacokinetics and Pharmacodynamics of Metformin in Healthy Male Adults

TypeinterventionalSponsorHyewon ChungRan2020 to 2020Enrolled16ConditionsHealthyArmsMetformin, Metformin + Nilotinib
3 · Its place in the literature

Who cites it

65 citing papers in PubMed, 2 syntheses or guidelines pooled it, 101 citations in OpenAlex.

  1. Pooled it
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  9. Pharmacogenetics and Molecular Ancestry ofPharmaceuticals (Basel, Switzerland) · 2025
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5 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

7 authors at 2 institutions in 2 countries.

Eugene C ChenDepartment of Bioengineering and Therapeutic Sciences (E.C.C., X.L., S.W.Y., E.G.G, S.L.S., K.M.G.) and Institute for Human Genetics (K.M.G.),University of California, San Francisco, California; and Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, China (L.C.).
Xiaomin LiangDepartment of Bioengineering and Therapeutic Sciences (E.C.C., X.L., S.W.Y., E.G.G, S.L.S., K.M.G.) and Institute for Human Genetics (K.M.G.),University of California, San Francisco, California; and Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, China (L.C.).
Sook Wah YeeDepartment of Bioengineering and Therapeutic Sciences (E.C.C., X.L., S.W.Y., E.G.G, S.L.S., K.M.G.) and Institute for Human Genetics (K.M.G.),University of California, San Francisco, California; and Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, China (L.C.).
Ethan G GeierDepartment of Bioengineering and Therapeutic Sciences (E.C.C., X.L., S.W.Y., E.G.G, S.L.S., K.M.G.) and Institute for Human Genetics (K.M.G.),University of California, San Francisco, California; and Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, China (L.C.).
Sophie L StockerDepartment of Bioengineering and Therapeutic Sciences (E.C.C., X.L., S.W.Y., E.G.G, S.L.S., K.M.G.) and Institute for Human Genetics (K.M.G.),University of California, San Francisco, California; and Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, China (L.C.).
Ligong ChenDepartment of Bioengineering and Therapeutic Sciences (E.C.C., X.L., S.W.Y., E.G.G, S.L.S., K.M.G.) and Institute for Human Genetics (K.M.G.),University of California, San Francisco, California; and Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, China (L.C.).
Kathleen M GiacominiDepartment of Bioengineering and Therapeutic Sciences (E.C.C., X.L., S.W.Y., E.G.G, S.L.S., K.M.G.) and Institute for Human Genetics (K.M.G.),University of California, San Francisco, California; and Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, China (L.C.) Kathy.giacomini@ucsf.edu.
University of California, San Francisco · USTsinghua University · CN

Funding

UCSF Liver Core CenterP30DK026743 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Holger Willenbring · 1986 to 2026
$30.7M
PHARMACOGENETICS OF MEMBRANE TRANSPORTERSU01GM061390 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI GIACOMINI, KATHLEEN M · 2000 to 2009
$29.2M
Research BaseP30DK063720 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KRUMMEL, MATTHEW F · 2003 to 2019
$21.8M
Pharmacogenomics of Membrane TransportersU19GM061390 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KWOK, PUI-YAN · 2010 to 2014
$16.3M
PHARMACEUTICAL SCIENCES AND PHARMACOGENOMICST32GM007175 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI AHITUV, NADAV, KROETZ, DEANNA L · 1985 to 2021
$7.1M
NIDDK NIH HHS P30 DK026743NIDDK NIH HHS P30 DK063720NIGMS NIH HHS T32 GM007175NIGMS NIH HHS T32-GM007175NIGMS NIH HHS U01 GM061390NIGMS NIH HHS U19 GM061390NIGMS NIH HHS U19-GM61390
6 · The paper itself

Abstract

Metformin, the most widely prescribed antidiabetic drug, requires transporters to enter tissues involved in its pharmacologic action, including liver, kidney, and peripheral tissues. Organic cation transporter 3 (OCT3, SLC22A3), expressed ubiquitously, transports metformin, but its in vivo role in metformin response is not known. Using Oct3 knockout mice, the role of the transporter in metformin pharmacokinetics and pharmacodynamics was determined. After an intravenous dose of metformin, a 2-fold decrease in the apparent volume of distribution and clearance was observed in knockout compared with wild-type mice (P < 0.001), indicating an important role of OCT3 in tissue distribution and elimination of the drug. After oral doses, a significantly lower bioavailability was observed in knockout compared with wild-type mice (0.27 versus 0.58, P < 0.001). Importantly, metformin's effect on the plasma glucose concentration-time curve was reduced in knockout compared with wild-type mice (12 versus 30% reduction, respectively, P < 0.05) along with its accumulation in skeletal muscle and adipose tissue (P < 0.05). Furthermore, the effect of metformin on phosphorylation of AMP activated protein kinase, and expression of glucose transporter type 4 was absent in the adipose tissue of Oct3(-/-) mice. Additional analysis revealed that an OCT3 3' untranslated region variant was associated with reduced activity in luciferase assays and reduced response to metformin in 57 healthy volunteers. These findings suggest that OCT3 plays an important role in the absorption and elimination of metformin and that the transporter is a critical determinant of metformin bioavailability, clearance, and pharmacologic action.

Indexed as

3' Untranslated RegionsAdipose TissueAnimalsBiological AvailabilityCell Line, TumorGene Expression RegulationGlucoseHCT116 CellsHealthy VolunteersHep G2 CellsHumansHypoglycemic AgentsInjections, IntraperitonealMaleMetforminMice3' Untranslated RegionsGlucoseHypoglycemic AgentsMetforminOrganic Cation Transporter 3Organic Cation Transport Proteins

Identifiers

PMID25920679
PMCPMC4468641
OpenAlexW2149135409

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.