title: Neurotoxicity and toxicokinetics of artelinic acid following repeated oral administration in rats.
abstract: 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 pharmacokinetic 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.
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, USA.
authors.forename: Yuanzheng
authors.initials: Y
authors.lastname: Si
authors.forename: Qigui
authors.initials: Q
authors.lastname: Li
authors.forename: Lisa
authors.initials: L
authors.lastname: Xie
authors.forename: Kent
authors.initials: K
authors.lastname: Bennett
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Weina
authors.forename: Steven
authors.initials: S
authors.lastname: Mog
authors.forename: Todd O
authors.initials: TO
authors.lastname: Johnson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D019540:Area Under Curve; D037621:Artemisinins / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity*; D001682:Biological Availability; D001933:Brain Stem / Q000187:drug effects / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005746:Gastric Emptying / Q000187:drug effects; D006207:Half-Life; D008297:Male; D015394:Molecular Structure; D009336:Necrosis; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012717:Sesquiterpenes / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity*; D013997:Time Factors; D014018:Tissue Distribution; D015431:Weight Loss / Q000187:drug effects
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; C062768:artelinic acid; C039060:artenimol