Sildenafil Bosentan

VASODILATOR ANTIHYPERTENSIVES-BOSENTAN SILDENAFIL 1 sildenafil levels Probable induction of metabolism Watch for poor response... 

Sitaxsentan is a potent and selective agent which inhibits ET-1 binding to ETA receptors (IC50 = 1.4 nM), while being essentially inactive at ETB receptors (IC50 = 9.8 pM).23 In the clinic, it was found to have excellent oral bioavailability (70-100%) and a terminal elimination half-life of 10 h, and is administered as a once daily 100 mg dose. It is highly protein bound in plasma (> 99%) and extensively metabolized in the liver to inactive metabolites, predominantly by CYPs 2C9 and 3A4. Excretion is 50 60% renal, with the balance in the feces.25 Sitaxsentan inhibits CYP 2C9, and was observed to increase exposure to warfarin by over twofold. The use of cyclosporine A is also contraindicated, but no interactions were observed with sildenafil.15 Sitaxsentan was well tolerated in trials, with only minor side effects reported. Reversible liver enzyme abnormalities were also observed, but less frequently than with bosentan.15 25... 

Clinically important, potentially hazardous interactions with alfuzosin, alprazolam, amphotericin B, anisindione, antacids, aprepitant, astemizole, atorvastatin, bosentan, ciclesonide, cimetidine, clorazepate, conivaptan, cyproterone, dasatinib, dexamethasone, dicumarol, didanosine, eplerenone, erythromycin, ethotoin, fentanyl, fesoterodine, fosamprenavir, fosphenytoin, grapefruit juice, HMG-CoA reductase inhibitors, imatinib, ixabepilone, lapatinib, lopinavir, lovastatin, mephenytoin, methylprednisolone, micafungin, midazolam, nilotinib, pimozide, prednisolone, prednisone, quinidine, rifampin, rimonabant, rivaroxaban, sildenafil, silodosin, simvastatin, sirolimus, solifenacin, temsirolimus, terfenadine, tolvaptan, triazolam, vardenafil, vinblastine, vincristine, warfarin... 

Treiber, A., Schneiter, R., Hausler, S. and Stieger, B. (2007) Bosentan is a substrate of human OATP1B1 and OATP1B3 inhibition of hepatic uptake as the common mechanism of its interactions with cyclosporin A, rifampicin, and sildenafil. Drug Metabolism and Disposition The Biological Fate of Chemicals, 35, 1400-1407. 

Mathai SC, Girgis RE, Fisher MR, et al. Addition of sildenafil to bosentan monotherapy in pulmonary arterial hypertension. Eur Respir J 2007 29(3) 469-75. 

Bosentan, epoprostenol, and sildenafil are used in pulmonary hypertension. 

On the basis of the 63% reduction in AUC seen with the moderate CYP3A4 indueer bosentan , (p.l274), the US manufacturer of sildenafil says that concurrent use with potent inducers of CYP3A4 such as rifampicin is predicted to cause a greater reduction in sildenafil levels. ... 

In 10 patients with pulmonary hypertension, bosentan 62.5 mg twice daily for one month decreased the AUC of a single 100-mg dose of sildenafil by 53% and increased its clearance 2.3-fold. After a second month of bosentan at an increased dose of 125 mg twice daily, the AUC of a single 100-mg dose of sildenafil was reduced by 69%, and the clearance increased 3.4-fold. The AUC of the primary metabolite, desmethyl-sildenafil, was also decreased in a dose-dependent manner by bosentan. In a further study in healthy subjects, the concurrent use of bosentan 125 mg twice daily and sildenafil 80 mg three times daily for 6 days decreased the AUC of sildenafil by 63%. ... 

Bosentan induces the cytochrome P450 isoenzyme CYP3A4 and CYP2C9, by which sildenafil is metabolised. 

This pharmacokinetic interaction is established and potentially clinically important. The efficacy of sildenafil is likely to be reduced in patients taking bosentan, and should be closely monitored. 

Paul GA, Gibbs JSR, Boobis AR, Abbas A, WiUdns MR. Bosentan decreases the plasm a concentration of sildenafil when coprescribed in pulmonary hypertension. BrJ Clin Pharmacol (2005) 60, 107-12. 

Bosentan The pharmacokinetic interaction of sildenafil and the dual endotheUn receptor antagonist bosentan, both of which are marketed for the treatment of pulmonary arterial hypertension, has been studied in 55 healthy men [31 ]. Bosentan reduced the Cnmx and AUCx of sildenafil, and sildenafil increased the corresponding values of bosentan. The clinical implications for combined therapy are not known. 

Burgess G, Hoogkamer H, Collings L, Dingemanse J. Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil. Eur J Clin Pharmacol 2008 64 43-50. 

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