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. 2013 Mar;29(1):27-34.
doi: 10.5487/TR.2013.29.1.027.

Embryotoxicity and toxicokinetics of the antimalarial artesunate in rats

Moon-Koo Chung  1 , Wook-Joon Yu, Jin-Soo Lee, Jong-Hwa Lee
Affiliations

Embryotoxicity and toxicokinetics of the antimalarial artesunate in rats

Moon-Koo Chung et al. Toxicol Res. 2013 Mar.

Abstract

This study was conducted to investigate the potential embryo-fetal toxicity and toxicokinetics of the antimalarial agent artesunate (ARTS) in Sprague-Dawley rats. Pregnant rats were administered ARTS daily from gestational day 6~15 via oral gavage, at test doses of 0, 2, 4, or 8 mg/kg (22 females per group). The fetuses were examined for external, visceral, and skeletal abnormalities on gestational day 20. With regard to the dams, there were no deaths, treatment-related clinical signs, changes in body weight, or food intake in any of the treatment groups. There were no treatment-related gross findings at necropsy in any treatment group. In the 8 mg/kg group, there was a decrease in gravid uterine weight and in the weight of female fetuses. There was also an increase in fetal deaths (primarily late resorptions) and an increase in post-implantation losses (37%) at 8 mg/kg. An increase in the incidence of visceral and skeletal variations at 4 and 8 mg/kg was observed. These defects included minor changes in the appearance of the kidney and thymus, as well as absent ribs or thoracic vertebrae. Toxicokinetics were assessed in a parallel study, using 4 mated females per group. Using liquid chromatography-mass spectrometry (LC-MS) analysis, the concentration of ARTS and its metabolite dihydroartemisinin (DHA) were quantified in plasma from rats on gestational days 5, 6, 10, and 15. Amniotic fluid was assayed for ARTS and DHA on gestational day 15. There was evidence of rapid conversion of ARTS to the metabolite DHA in maternal plasma, since ARTS could not be consistently detected in plasma at the three doses tested. ARTS and DHA were not detected in amniotic fluid at gestational day 15, indicating limited placental transfer of the two agents. The embryofetal no-observable-adverse-effect level (NOAEL) of the test item was considered to be 8 mg/kg/day for dams, and 2 mg/kg/day for embryo-fetal development.

Keywords: Antimalarial agent; Artesunate (ARTS); Embryotoxicity; Rats; Toxicokinetics.

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Figures

Fig. 1.
Fig. 1.. Chemical structure of artesunate (ARTS) and its active and major metabolite, dihydroartemisinin (DHA).
Fig. 2.
Fig. 2.. Plot of mean maternal DHA plasma concentration vs. time for rat embryo-fetal toxicokinetic study.
Fig. 3.
Fig. 3.. Plot of mean (± SD) maternal ARTS and DHA plasma concentrations on gestation day 15 vs. ARTS dose in pregnant female rats.
See this image and copyright information in PMC

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