A non-linear pharmacokinetic-pharmacodynamic relationship of metformin in healthy volunteers: An open-label, parallel group, randomized clinical study

PLoS One. 2018 Jan 17;13(1):e0191258. doi: 10.1371/journal.pone.0191258. eCollection 2018.

Abstract

Background: The aim of this study was to explore the pharmacokinetic-pharmacodynamic (PK-PD) relationship of metformin on glucose levels after the administration of 250 mg and 1000 mg of metformin in healthy volunteers.

Methods: A total of 20 healthy male volunteers were randomized to receive two doses of either a low dose (375 mg followed by 250 mg) or a high dose (1000 mg followed by 1000 mg) of metformin at 12-h intervals. The pharmacodynamics of metformin was assessed using oral glucose tolerance tests before and after metformin administration. The PK parameters after the second dose were evaluated through noncompartmental analyses. Four single nucleotide polymorphisms in MATE1, MATE2-K, and OCT2 were genotyped, and their effects on PK characteristics were additionally evaluated.

Results: The plasma exposure of metformin increased as the metformin dose increased. The mean values for the area under the concentration-time curve from dosing to 12 hours post-dose (AUC0-12h) were 3160.4 and 8808.2 h·μg/L for the low- and high-dose groups, respectively. Non-linear relationships were found between the glucose-lowering effect and PK parameters with a significant inverse trend at high metformin exposure. The PK parameters were comparable among subjects with the genetic polymorphisms.

Conclusions: This study showed a non-linear PK-PD relationship on plasma glucose levels after the administration of metformin. The inverse relationship between systemic exposure and the glucose-lowering effect at a high exposure indicates a possible role for the intestines as an action site for metformin.

Trial registration: ClinicalTrials.gov NCT02712619.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Blood Glucose / metabolism
  • Dose-Response Relationship, Drug
  • Glucose Tolerance Test
  • Healthy Volunteers
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / pharmacokinetics*
  • Hypoglycemic Agents / pharmacology*
  • Male
  • Metformin / administration & dosage
  • Metformin / pharmacokinetics*
  • Metformin / pharmacology*
  • Models, Biological
  • Nonlinear Dynamics
  • Organic Cation Transport Proteins / genetics
  • Organic Cation Transport Proteins / metabolism
  • Organic Cation Transporter 2 / genetics
  • Organic Cation Transporter 2 / metabolism
  • Pharmacogenomic Variants
  • Polymorphism, Single Nucleotide
  • Young Adult

Substances

  • Blood Glucose
  • Hypoglycemic Agents
  • Organic Cation Transport Proteins
  • Organic Cation Transporter 2
  • SLC22A2 protein, human
  • SLC47A1 protein, human
  • SLC47A2 protein, human
  • Metformin

Associated data

  • ClinicalTrials.gov/NCT02712619

Grants and funding

This research was funded by the Seoul National University and Bundang Hospital Research Fund [grant 06-2013-101], and supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number : HI14C2770). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.