Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension.
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.
Paul
Gideon A
GA
Experimental Medicine & Toxicology, Imperial College London, London, UK.
Gibbs
J Simon R
JS
Boobis
Alan R
AR
Abbas
Allifia
A
Wilkins
Martin R
MR
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
D000959:Antihypertensive Agents; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013449:Sulfonamides; D013450:Sulfones; D000068677:Sildenafil Citrate; D000077300:Bosentan