28‐Day Repeated Dose Toxicity and Toxicokinetics Study on Dihydroartemisinin (DHA) in SD Rats

ABSTRACT Dihydroartemisinin (DHA) is an effective antimalarial drug with potential antitumor efficacy, yet toxicological information is limited. The present study was designed to evaluate the potential toxicity of oral DHA. DHA was administered orally by gavage to SD rats at doses of 0, 25, 50, and 75/60 mg/kg b.w./day for 28 days, followed by a 4‐week recovery period. Concomitant toxicokinetics was also evaluated. Due to potential toxicity affecting survival, only the female top dose was adjusted from 75 to 60 mg/kg on study day 14 (D14). Female rats in the low‐dose group and male rats in the low‐ and medium‐dose groups did not show any signs of toxicity. In contrast, male rats in the high‐dose group and female rats in the medium‐ and high‐dose groups showed significant toxic effects, including weight loss, hair loss, and gastrointestinal reactions (soft stools, perianal dirt, and fecal abnormalities). At the end of administration, female rats in the 75/60 (dose‐adjusted) mg/kg dose group had significantly higher reticulocytes (Ret% and RETIC) and alanine aminotransferase (ALT), increased liver weights, and significantly lower hemoglobin (HGB). In addition, histopathology showed mild vacuolation of hepatocytes. These findings suggest that female rats have a greater toxic response than males, and toxicokinetics further demonstrate this sex difference. However, the toxic effects of DHA were reversed at the end of the 4‐week recovery period. Therefore, the liver was identified as the primary target organ. The no‐observed‐adverse‐effect‐level (NOAEL) was 25 and 50 mg/kg b.w./day in female and male rats, respectively.