title: Clarithromycin substantially increases steady-state bosentan exposure in healthy volunteers.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Markert
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Schweizer
authors.forename: Regina
authors.initials: R
authors.lastname: Hellwig
authors.forename: Theresia
authors.initials: T
authors.lastname: Wirsching
authors.forename: Klaus-Dieter
authors.initials: KD
authors.lastname: Riedel
authors.forename: Juergen
authors.initials: J
authors.lastname: Burhenne
authors.forename: Johanna
authors.initials: J
authors.lastname: Weiss
authors.forename: Gerd
authors.initials: G
authors.lastname: Mikus
authors.forename: Walter E
authors.initials: WE
authors.lastname: Haefeli
mesh_terms: D000328:Adult; D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics; D000077300:Bosentan; D017291:Clarithromycin / Q000494:pharmacology*; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions / Q000235:genetics*; D065128:Endothelin Receptor Antagonists / Q000493:pharmacokinetics*; D005260:Female; D005838:Genotype; D064368:Healthy Volunteers; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics; D027361:Organic Anion Transporters / Q000235:genetics; D013449:Sulfonamides / Q000493:pharmacokinetics*
chemical_list: D014151:Anti-Anxiety Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D065128:Endothelin Receptor Antagonists; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D013449:Sulfonamides; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017291:Clarithromycin; D000077300:Bosentan; D008874:Midazolam
keywords: CYP2C9; SLCO1B1; bosentan; clarithromycin; pharmacokinetics; polymorphism