Acute effect of sildenafl is maintained in pulmonary arterial hypertension patients chronically treated with bosentan

Abstract

The chronic use of bosentan has been reported to reduce the plasma concentration of sildenafl. However, it remains unclear how sildenafl exerts the effect at reduced concentrations in pulmonary arterial hypertension (PAH) patients chronically treated with bosentan. We examined the hemodynamic effects of sildenafl (50 mg) in 8 Japanese patients with PAH, and simultaneously measured the plasma concentration of sildenafl ([Sil]) and its major metabolite, desmethylsildenafl ([Des]). The overall effects of sildenafl were 12.4% decrease in mean pulmonary arterial pressure, 19.9% increase in cardiac index (CI), and 25% reduction in derived pulmonary vascular resistance (PVR). When the patients were divided into two groups, a group with bosentan pretreatment [BOS (+), n = 4] and a group without bosentan pretreatment [BOS (-), n = 4], both [Sil] and [Des] were lower at the peak concentration (Cmax) and the area under the plasma concentration versus time curve (AUC0-6h), and the time to reach Cmax was longer in BOS (+), although only the difference in AUC0-6h of [Des] reached statistical significance (P = 0.02). In spite of lower concentration, the effect of sildenafl on CI was maintained in the BOS (+) group, while the decrease in PVR was less marked. Sildenafl acutely dilated the pulmonary artery and increased CI in the PAH patients. These effects were still observed or maintained in the PAH patients chronically treated with bosentan, even when [Sil] was reduced.