In Vitro Investigation, Pharmacokinetics, and Disposition of Imeglimin, a Novel Oral Antidiabetic Drug, in Preclinical Species and Humans

Drug Metab Dispos. 2020 Dec;48(12):1330-1346. doi: 10.1124/dmd.120.000154. Epub 2020 Oct 5.


Imeglimin is a novel oral antidiabetic drug for treatment of type 2 diabetes that targets mitochondrial bioenergetics. Its pharmacokinetics absorption characteristics, metabolism, distribution, and elimination were assessed through several in vitro and in vivo experiments in both animals and humans. Its potential to induce drug-drug interactions was also extensively assessed. Imeglimin is a small cationic compound with an intermediate intestinal permeability. Its absorption mechanism involves an active transport process in addition to passive paracellular absorption. Absorption was good (50%-80%) in vivo across several species but decreased with increasing dose, probably because of saturation of active transport. After absorption, imeglimin was rapidly and largely distributed to internal organs. Plasma protein binding was low, which can explain the rapid distribution to organs observed in all species. In animals and humans, imeglimin was largely excreted unchanged in urine, indicating a low extent of metabolism. Unchanged drug was the main circulating entity in plasma, and none of the identified metabolites were unique to human. Imeglimin renal clearance was higher than creatinine clearance, indicating that it was actively secreted into urine. There was no evidence that it had the potential to cause cytochrome P450 inhibition or induction. It was shown to be a substrate of organic cation transporter (OCT) 1, OCT2, multidrug and toxin extrusion (MATE) 1, and MATE2-K and an inhibitor of OCT1, OCT2, and MATE1; as a consequence, corresponding clinical drug-drug interaction studies were performed and confirmed the absence of relevant interactions with substrates or inhibitors of these transporters. SIGNIFICANCE STATEMENT: Imeglimin is absorbed through a passive and active mechanism, which can be saturated. It is rapidly and largely distributed to internal organs and mainly excreted unchanged in urine. It is poorly metabolized and has no cytochrome P450 inhibition or induction potential. Imeglimin is a substrate of MATE2-K and also a substrate and an inhibitor of OCT1, OCT2, and MATE1 transporters; however, there are no clinically significant interactions when imeglimin is coadministered with either a substrate or an inhibitor of these transporters.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravenous
  • Administration, Oral
  • Adult
  • Animals
  • Caco-2 Cells
  • Cytochrome P-450 Enzyme Inhibitors / pharmacology
  • Cytochrome P-450 Enzyme System / metabolism
  • Diabetes Mellitus, Type 2 / drug therapy
  • Dogs
  • Drug Evaluation, Preclinical
  • Drug Interactions
  • Female
  • HEK293 Cells
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / pharmacokinetics*
  • Intestinal Absorption / drug effects
  • Male
  • Middle Aged
  • Organic Cation Transport Proteins / agonists
  • Organic Cation Transport Proteins / antagonists & inhibitors
  • Organic Cation Transport Proteins / metabolism
  • Rats
  • Triazines / administration & dosage
  • Triazines / pharmacokinetics*


  • Cytochrome P-450 Enzyme Inhibitors
  • Hypoglycemic Agents
  • Organic Cation Transport Proteins
  • Triazines
  • Cytochrome P-450 Enzyme System
  • imeglimin