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. 2005 Jul;60(1):107-12.
doi: 10.1111/j.1365-2125.2005.02383.x.

Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension

Gideon A Paul  1 , J Simon R Gibbs, Alan R Boobis, Allifia Abbas, Martin R Wilkins
Affiliations

Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension

Gideon A Paul et al. Br J Clin Pharmacol. 2005 Jul.

Abstract

Aims: 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.

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Figures

Figure 1
Figure 1
Mean plasma concentration-time curves for (A) sildenafil and (B) desmethylsildenafil following administration of sildenafil 100 mg alone (▴) after 4 weeks’ bosentan 62.5 mg b.d. (×) and after 4 weeks’ bosentan 125 mg b.d. (•). n = 10
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