Clarithromycin substantially increases steady-state bosentan exposure in healthy volunteers

Br J Clin Pharmacol. 2014 Jan;77(1):141-8. doi: 10.1111/bcp.12177.


Aims: The aim of this study was to assess the effect of the cytochrome P450 (CYP) 3A4 and organic anion-transporting polypeptide (OATP) 1B1 inhibitor clarithromycin on the pharmacokinetics of bosentan. We also aimed to evaluate the impact of CYP2C9 and SLCO1B1 (encoding for OATP1B1) genotypes and their combination.

Methods: We assessed the effect of the OATP and CYP3A inhibitor clarithromycin on bosentan pharmacokinetics at steady state and concurrently quantified changes of CYP3A activity using midazolam as a probe drug. Sixteen healthy volunteers received therapeutic doses of bosentan (125 mg twice daily) for 14 days and clarithromycin (500 mg twice daily) concomitantly for the last 4 days, and bosentan pharmacokinetics was assessed on days 1, 10 and 14.

Results: Clarithromycin significantly increased bosentan area under the plasma concentration-time curve of the dosing interval 3.7-fold and peak concentration 3.8-fold in all participants irrespective of the genotype. Clarithromycin also reduced CYP3A activity (midazolam clearance) in all participants; however, these changes were not correlated to the changes of bosentan clearance.

Conclusions: Clarithromycin substantially increases the exposure to bosentan, suggesting that dose reductions may be necessary.

Keywords: CYP2C9; SLCO1B1; bosentan; clarithromycin; pharmacokinetics; polymorphism.

Publication types

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

MeSH terms

  • Adult
  • Anti-Anxiety Agents / pharmacokinetics
  • Bosentan
  • Clarithromycin / pharmacology*
  • Cytochrome P-450 CYP2C9 / genetics
  • Cytochrome P-450 CYP3A / genetics
  • Cytochrome P-450 CYP3A Inhibitors / pharmacology*
  • Drug Interactions / genetics*
  • Endothelin Receptor Antagonists / pharmacokinetics*
  • Female
  • Genotype
  • Healthy Volunteers
  • Humans
  • Liver-Specific Organic Anion Transporter 1
  • Male
  • Midazolam / pharmacokinetics
  • Organic Anion Transporters / genetics
  • Sulfonamides / pharmacokinetics*


  • Anti-Anxiety Agents
  • Cytochrome P-450 CYP3A Inhibitors
  • Endothelin Receptor Antagonists
  • Liver-Specific Organic Anion Transporter 1
  • Organic Anion Transporters
  • SLCO1B1 protein, human
  • Sulfonamides
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Clarithromycin
  • Bosentan
  • Midazolam