indication

Investigated for use/treatment in pulmonary hypertension, connective tissue diseases, hypertension, and congestive heart failure.

pharmacology

Sitaxentan belongs to a class of drugs known as endothelin receptor antagonists (ERAs). Patients with PAH have elevated levels of endothelin, a potent blood vessel constrictor, in their plasma and lung tissue. Sitaxentan blocks the binding of endothelin to its receptors, thereby negating endothelin's deleterious effects.

mechanism of action

Sitaxentan is a competitive antagonist of endothelin-1 at the endothelin-A (ET-A) and endothelin-B (ET-B) receptors. Under normal conditions, endothelin-1 binding of ET-A or ET-B receptors causes pulmonary vasoconstriction. By blocking this interaction, Sitaxentan decreases pulmonary vascular resistance. Sitaxentan has a higher affinity for ET-A than ET-B.

biotransformation

Hepatic (CYP2C9- and CYP3A4-mediated)

absorption

70-100%

half life

10 hours

route of elimination

Renal (50 to 60%) Fecal (40 to 50%)

drug interactions

Carisoprodol: Strong CYP2C19 inhibitors such as sitaxentan may decrease the metabolism of CYP2C19 substrates such as carisoprodol. Consider an alternative for one of the interacting drugs in order to avoid toxicity of the substrate. Some combinations are specifically contraindicated by manufacturers. Suggested dosage adjustments are also offered by some manufacturers. Please review applicable package inserts. Monitor for increased effects of the CYP substrate if a CYP inhibitor is initiated/dose increased, and decreased effects if a CYP inhibitor is discontinued/dose decreased.

Tamoxifen: Sitaxsentan may reduce clearance rate of Tamoxifen. Monitor for changes in therapeutic/adverse effects of Tamoxifen if Sitaxsentan is initiated, discontinued or dose changed.

Tamsulosin: Sitaxsentan, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Sitaxsentan is initiated, discontinued, or dose changed.

Tolbutamide: Sitaxsentan, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Tolbutamide, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in Tolbutamide therapeutic and adverse effects if Sitaxsentan is initiated, discontinued or dose changed.

Tolterodine: Sitaxsentan may decrease the metabolism and clearance of Tolterodine. Adjust Tolterodine dose and monitor for efficacy and toxicity.

Torasemide: Sitaxsentan, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Sitaxsentan is initiated, discontinued or dose changed.

Tramadol: Sitaxsentan may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Trazodone: The CYP3A4 inhibitor, Sitaxsenten, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Norfloxacin is initiated, discontinued or dose changed.

Trimethoprim: The strong CYP2C9 inhibitor, Sitaxsentan, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Sitaxsentan is initiated, discontinued or dose changed.

Trimipramine: The strong CYP2C19 inhibitor, Sitaxsentan, may decrease the metabolism and clearance of Trimipramine, a CYP2D6 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimipramine if Sitaxsentan is initiated, discontinued or dose changed.

Voriconazole: Sitaxsentan, a strong CYP2C9 inhibitor, may increase the serum concentration of voriconazole by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of voriconazole if sitaxsentan is initiated, discontinued or dose changed.

Warfarin: Sitaxentan, a strong CYP2C9 inhibitor, may decrease the metabolism of warfarin. Warfarin doses should be decreased by 80% upon initiated of concomitant therapy. Monitor for changes in the therapeutic and adverse effects of warfarin if sitaxentan is initiated, discontinued or dose changed.

Zafirlukast: Sitaxentan, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of zafirlukast. Consider alternate therapy or monitor for changes in zafirlukast therapeutic and adverse effects if sitaxentan is initiated, discontinued or dose changed.