The enhancement of cardiac toxicity by concomitant administration of Berberine and macrolides

Eur J Pharm Sci. 2015 Aug 30;76:149-55. doi: 10.1016/j.ejps.2015.05.009. Epub 2015 May 11.


As is well-known, hERG plays an essential role in phase III repolarization of cardiac action potentials. Blocking of hERG channels can lead to LQTS. Inhibition of the metabolism of CYPs activities may elevate plasma levels, to further increase accumulation of drug on cardiac. The elevated serum levels may however elicit unexpected toxicities. Therefore, the inhibition tests of hERG and CYP are central to the preclinical studies because they may lead to severe cardiac toxicity. Berberine is widely used as an antibacterial agent and often combined with macrolides to treat gastropathy. Our objective was to assess cardiac toxicity during the combined use of Berberine with macrolides. (1) Azithromycin reduced hERG currents by accelerated channel inactivation. (2) The combination of Berberine with Azithromycin reduced hERG currents, producing an inhibitive effect stronger than use of a single drug alone, due to the high binding affinity for the onset of inactivation. (3) When cells were perfused concomitantly with Berberine and Clarithromycin, they showed a stronger inhibitive effect on hERG currents by decreasing the time constant for the onset of inactivation. (4) The combined administration of Berberine with Clarithromycin had a powerful inhibitive effect on CYP3A activities than use of a single drug alone. Collectively, these results demonstrated that concomitant use of Berberine with macrolides may require close monitoring because of potential drug toxicities, especially cardiac toxicity.

Keywords: Azithromycin (AZM); Berberine (BBR); Cardiac toxicity; Clarithromycin (CLR); Cytochrome P450 (CYP); hERG.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / toxicity*
  • Azithromycin / toxicity*
  • Berberine / toxicity*
  • Clarithromycin / toxicity*
  • Cytochrome P-450 CYP3A / metabolism
  • Cytochrome P-450 CYP3A Inhibitors / toxicity*
  • Drug Synergism
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors*
  • Ether-A-Go-Go Potassium Channels / genetics
  • Ether-A-Go-Go Potassium Channels / metabolism
  • HEK293 Cells
  • Heart Diseases / chemically induced*
  • Heart Diseases / metabolism
  • Heart Diseases / physiopathology
  • Humans
  • Male
  • Membrane Potentials
  • Microsomes, Liver / enzymology
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism
  • Potassium Channel Blockers / toxicity*
  • Rats
  • Rats, Wistar
  • Risk Assessment
  • Transfection


  • Anti-Bacterial Agents
  • Cytochrome P-450 CYP3A Inhibitors
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • KCNH2 protein, human
  • Potassium Channel Blockers
  • Berberine
  • Azithromycin
  • Cyp3a2 protein, rat
  • Cytochrome P-450 CYP3A
  • Clarithromycin