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Neurotoxicity and Toxicokinetics of Artelinic Acid Following Repeated Oral Administration in Rats

Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA

Steven Mog

Comparative Pathology Division (VSDP), Veterinary Sciences Department Armed Forces Radiobiology Research Institute (AFRRI), Bethesda, Maryland, USA

Todd O. Johnson

Department of Pathology, Naval Medical Research Center, Silver Spring, Maryland, USA

Correspondence: Address correspondence to Dr. Qigui Li, Department of Pharmacology, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring MD, 20910, USA. E-mail:qigui.li{at}na.amedd.army.mil

Neurotoxicity secondary to oil-soluble artemisinins has been reported in various animal species. The onset of neurotoxicity and toxicokinetics of oral artelinic acid (AL), a water-soluble artemisinin, were investigated. After dose range study, rats were dosed at either 160 mg/kg daily for 9 consecutive days or at 288 mg/kg once every other day for five doses, so that the total dose (1440 mg/kg) and duration (9 days) were identical. Neuronal damage of varying severity was identified beginning as early as 1 day after completing dosing and continued for up to 10 days post dosing. Neuronal injury was most severe 7 days after the last treatment in each of the two dosing regimens. The rats dosed with 160 mg/kg of AL daily showed moderate neurotoxicity and lost 22% of their body weight during treatment. Compared with the first dose, the toxicokinetic profile of this regimen changed significantly, with the elimination half-life increasing 3.82-fold and the volume of distribution increasing 5.23-fold on the last day of dosing. In the animals treated with AL at 288 mg/kg every other day for 5 doses, minimal neuronal degeneration (severity score 1.17) was identified and the body weight was only 8% loss. Furthermore, there were no obvious differences in the pharniacokinetic parameters between first and last dosing days with this regimen. Additionally, a progressively drug retention in stomach and drug accretion in blood were only found in rats treated with 160 mg/kg daily for 9 days. These results imply that delayed gastric emptying resulted in AL accumulation in blood and prolonged a neurotoxic exposure time (186 h) in 160 mg/kg rats when compared to that (75 h) in 288 mg/kg animals. Therefore, the drug exposure time is a key factor in the neurotoxicity induced by AL.

Key Words: Artelinic Acid • Exposure Time • Neurotoxicity • Oral Regimen • Rats • Toxicokinetics

International Journal of Toxicology, Vol. 26, No. 5, 401-410 (2007)
DOI: 10.1080/10915810701582913


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