An overview of the preclinical toxicity and potential carcinogenicity of sitaxentan (Thelin®), a potent endothelin receptor antagonist developed for pulmonary arterial hypertension

► Sitaxentan preclinical safety was assessed in mice, rats, and dogs. ► Coagulopathy, increased serum alkaline phosphatase, hepatic hypertrophy and decreased blood parameters were observed. ► Effects occurred at exposures substantially greater than human therapeutic exposure. ► Sitaxentan showed a low potential for testicular and hepatic toxicity and was not carcinogenic. ► The pattern of sitaxentan toxicity could be characterized as an exaggeration of its pharmacological mechanism of action.