26-Week Repeated-Dose Toxicity Study of a Novel Antiarrhythmic Drug Sulcardine Sulfate in Sprague-Dawley Rats.

Abstract

Sulcardine sulfate (Sul) is a novel antiarrhythmic agent blocking multiple channels and exhibits unique pharmacological properties such as lower APD-dependent prolongation and reduced arrhythmia risk. Sul is currently in Phase III clinical trials, yet studies on its long-term toxicological profile and potential target organs remain unexplored. This study investigated the related toxicity of Sul in Sprague Dawley (SD) rats through repeated oral administration for 26 weeks, followed by a 4-week recovery period. Consistent with the clinical intended mode of administration, Sul was administered via oral gavage at daily doses of 0, 175, 350, and 700/525 mg/kg in rats. On account of clinically observed body weight loss of male and female rats in the high-dose group compared with the control group, with one female rat in the high-dose group dying after 8 weeks of administration, the high dose was adjusted to 525 mg/kg. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in male rats significantly increased in the medium- and high-dose groups, whereas female rats in these groups showed a significant rise in alkaline phosphatase (ALP) levels, accompanied by varying degrees of weight gain in the liver and lungs. Additionally, brownish-red pigment deposition was observed in hepatocytes and Kupffer cells across all dosing groups, along with foam cell deposition in the alveolar cavities. Concomitant toxicokinetics showed that the drug accumulated to some extent in the animals. Consequently, the liver and lungs were identified as potential target organs, and the no observed adverse effect level (NOAEL) was determined to be 175 mg/kg.