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.
Andersen, H., S. Larsen, H. Spliid, and N. D. Christensen. 1999. “Multivariate Statistical Analysis of Organ Weights in Toxicity Studies.” Toxicology 136, no. 2–3: 67–77. https://doi.org/10.1016/s0300‐483x(99)00056‐6.
Bailey, S. A., R. H. Zidell, and R. W. Perry. 2004. “Relationships Between Organ Weight and Body/Brain Weight in the Rat: What Is the Best Analytical Endpoint?.” Toxicologic Pathology 32, no. 4: 448–466. https://doi.org/10.1080/01926230490465874.
Buragohain, P., B. Saikia, N. Surineni, N. C. Barua, A. K. Saxena, and N. Suri. 2014. “Synthesis of a Novel Series of Artemisinin Dimers With Potent Anti‐Cancer Activity Involving Sonogashira Cross‐Coupling Reaction.” Bioorganic & Medicinal Chemistry Letters 24, no. 1: 237–239. https://doi.org/10.1016/j.bmcl.2013.11.032.
Chen, T., M. Li, R. Zhang, and H. Wang. 2009. “Dihydroartemisinin Induces Apoptosis and Sensitizes Human Ovarian Cancer Cells to Carboplatin Therapy.” Journal of Cellular and Molecular Medicine 13, no. 7: 1358–1370. https://doi.org/10.1111/j.1582‐4934.2008.00360.x.
Dai, X., X. Zhang, W. Chen, et al. 2021. “Dihydroartemisinin: A Potential Natural Anti‐Cancer Drug.” International Journal of Biological Sciences 17, no. 2: 603–622. https://doi.org/10.7150/ijbs.50364.
Holohan, C., S. Van Schaeybroeck, D. B. Longley, and P. G. Johnston. 2013. “Cancer Drug Resistance: An Evolving Paradigm.” Nature Reviews. Cancer 13, no. 10: 714–726. https://doi.org/10.1038/nrc3599.
Klayman, D. L. 1985. “Qinghaosu (Artemisinin): An Anti‐Malarial Drug From China.” Science 228, no. 4703: 1049–1055. https://doi.org/10.1126/science.3887571.
Lin, A. J., M. Lee, and D. L. Klayman. 1989. “Anti‐Malarial Activity of New Water‐Soluble Dihydroartemisinin Derivatives. 2. Stereospecificity of the Ether Side Chain.” Journal of Medicinal Chemistry 32, no. 6: 1249–1252. https://doi.org/10.1021/jm00126a017.
Ramaswamy, R. S., N. Prathyusha, R. Saranya, et al. 2012. “Acute Toxicity and the 28‐Day Repeated Dose Study of a Siddha Medicine Nuna Kadugu in Rats.” BMC Complementary and Alternative Medicine 12: 190. https://doi.org/10.1186/1472‐6882‐12‐190.
Singh, N. P., and H. Lai. 2001. “Selective Toxicity of Dihydroartemisinin and Holotransferrin Toward Human Breast Cancer Cells.” Life Sciences 70, no. 1: 49–56. https://doi.org/10.1016/s0024‐3205(01)01372‐8.
Sung, H., J. Ferlay, R. L. Siegel, et al. 2021. “Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.” CA: A Cancer Journal for Clinicians 71, no. 3: 209–249. https://doi.org/10.3322/caac.21660.
Tu, Y. 2011. “The Discovery of Artemisinin (Qinghaosu) and Gifts From Chinese Medicine.” Nature Medicine 17, no. 10: 1217–1220. https://doi.org/10.1038/nm.2471.
Xu, C. C., T. Deng, M. L. Fan, W. B. Lv, J. H. Liu, and B. Y. Yu. 2016. “Synthesis and in Vitro Anti‐Tumor Evaluation of Dihydroartemisinin‐Cinnamic Acid Ester Derivatives.” European Journal of Medicinal Chemistry 107: 192–203. https://doi.org/10.1016/j.ejmech.2015.11.003.
