title: Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension.
abstract: OBJECTIVE
  To determine whether bosentan decreases the plasma concentration of sildenafil in patients with pulmonary arterial hypertension.
  
  
  METHODS
  Ten patients (aged 39-77 years) with pulmonary arterial hypertension in WHO functional class III received bosentan 62.5 mg twice daily for 1 month, then 125 mg twice daily for a second month. Sildenafil 100 mg was given as a single dose before starting bosentan (visit 1) and at the end of each month of bosentan treatment (visits 2 and 3). Sildenafil and its primary metabolite, desmethylsildenafil, were measured in plasma at 0 h and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18 and 24 h using liquid chromatography-tandem mass spectrometry. Statistical analysis was by repeated measures anova, using log transformed data where appropriate.
  
  
  RESULTS
  Treatment with bosentan 62.5 mg twice daily for 4 weeks was associated with a two-fold increase in sildenafil clearance/F and a 50% decrease in the AUC (P < 0.001). Increasing the dose of bosentan to 125 mg twice daily led to a further increase in sildenafil oral clearance and decrease in the AUC (P < 0.001 vs. 62.5 mg bosentan). The ratio of AUC on bosentan treatment relative to that of visit 1 was 0.47 [95% confidence interval (CI) 0.36, 0.61] for visit 2 and 0.31 (95% CI 0.23, 0.41) for visit 3 (P < 0.001). Sildenafil C(max) fell from 759 ng ml(-1) on visit 1 to 333 ng ml(-1) on visit 3 (P < 0.01) and there was a significant decrease in the plasma half-life of sildenafil on the higher bosentan dose (P < 0.05). The AUC and plasma half-life of desmethylsildenafil was also decreased by bosentan in a dose-dependent manner (P < 0.01).
  
  
  CONCLUSIONS
  Bosentan significantly decreases the plasma concentration of sildenafil when coadministered to patients with pulmonary hypertension.
authors.affiliation: Experimental Medicine & Toxicology, Imperial College London, London, UK.
authors.forename: Gideon A
authors.initials: GA
authors.lastname: Paul
authors.forename: J Simon R
authors.initials: JS
authors.lastname: Gibbs
authors.forename: Alan R
authors.initials: AR
authors.lastname: Boobis
authors.forename: Allifia
authors.initials: A
authors.lastname: Abbas
authors.forename: Martin R
authors.initials: MR
authors.lastname: Wilkins
mesh_terms: D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D019540:Area Under Curve; D000077300:Bosentan; D004359:Drug Therapy, Combination; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010726:Phosphodiesterase Inhibitors / Q000097:blood*; D010879:Piperazines / Q000097:blood*; D011687:Purines; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use*; D013450:Sulfones
chemical_list: D000959:Antihypertensive Agents; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013449:Sulfonamides; D013450:Sulfones; D000068677:Sildenafil Citrate; D000077300:Bosentan