Organic cation transporter and multidrug and toxin extrusion 1 co-mediated interaction between metformin and berberine

Eur J Pharm Sci. 2019 Jan 15;127:282-290. doi: 10.1016/j.ejps.2018.11.010. Epub 2018 Nov 11.

Abstract

Metformin and berberine are often combined for treating diabetes. In the present study, we evaluated the drug-drug pharmacokinetic interaction between metformin and berberine after oral co-administration in vivo and the underlying mechanism. As revealed by comparison with the metformin-only group, berberine significantly decreased the maximum plasma concentration (Cmax), area under the curve from 0 to 4 h (AUC0-4h), and urinary and bile excretion, and increased the kidney tissue concentration of metformin in rats. The non-everted intestinal sac study showed that berberine inhibited the absorption of metformin, and in transfected Madin-Darby canine kidney (MDCK)-rat organic cation transporter 1 (MDCK-rOCT1), MDCK-rat organic cation transporter 2 (MDCK-rOCT2), and MDCK-rat multidrug and toxin extrusion 1 (MDCK-rMATE1) cells, berberine significantly inhibited metformin transport mediated by OCT1, OCT2, and MATE1 in a concentration-dependent manner with half-maximal inhibitory concentration (IC50) values of 18.8, 1.02, and 10.7 μM, respectively. In contrast, co-administration of metformin increased the Cmax and AUC0-4h of berberine with no significant difference in pharmacokinetics parameters between co-administration and berberine-only groups. Furthermore, metformin increased kidney and liver concentrations and reduced the urinary and biliary excretion of berberine. Metformin (≥1 or ≥0.3 mM) decreased berberine transport in MDCK-rOCT1, MDCK-rOCT2, and MDCK-rMATE1 cells. However, metformin did not affect berberine concentration in MDCK-multidrug resistance protein 1 cells. These results suggest that the combination of metformin and berberine induced a pharmacokinetic interaction by cooperatively inhibiting OCT and MATE1-mediated transport.

Keywords: Berberine; Metformin; Multidrug and toxin extrusion; Organic cation transporter; Pharmacokinetic interaction.

MeSH terms

  • Adipose Tissue / metabolism
  • Animals
  • Antiporters / genetics
  • Antiporters / metabolism*
  • Berberine / blood
  • Berberine / pharmacokinetics*
  • Catecholamine Plasma Membrane Transport Proteins / genetics
  • Catecholamine Plasma Membrane Transport Proteins / metabolism*
  • Dogs
  • Drug Interactions
  • Female
  • Hypoglycemic Agents / blood
  • Hypoglycemic Agents / pharmacokinetics*
  • Intestinal Mucosa / metabolism
  • Kidney / metabolism
  • Liver / metabolism
  • Madin Darby Canine Kidney Cells
  • Male
  • Metformin / blood
  • Metformin / pharmacokinetics*
  • Muscle, Skeletal / metabolism
  • Organic Cation Transport Proteins / genetics
  • Organic Cation Transport Proteins / metabolism*
  • Organic Cation Transporter 2 / genetics
  • Organic Cation Transporter 2 / metabolism*
  • Rats, Sprague-Dawley

Substances

  • Antiporters
  • Catecholamine Plasma Membrane Transport Proteins
  • Hypoglycemic Agents
  • Organic Cation Transport Proteins
  • Organic Cation Transporter 2
  • Slc22a1 protein, rat
  • Slc47a1 protein, rat
  • Berberine
  • Metformin