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Embryotoxicity of artesunate in animal species related to drug tissue distribution and toxicokinetic profiles. | LitMetric

Embryotoxicity of artesunate in animal species related to drug tissue distribution and toxicokinetic profiles.

Birth Defects Res B Dev Reprod Toxicol

Department of Pharmacology, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910-7500, USA.

Published: August 2008

AI Article Synopsis

Article Abstract

Background: Injectable artesunate (AS) can cause fetal death and teratogenic effects in animals at levels below the human therapeutic dose. Similar toxicity has also been found for oral artemisinins in various animal species, but has not been found in humans.

Methods: Studies on tissue distribution (5 mg/kg) and toxicokinetics (TK, 30 mg/kg x 3) were conducted in pregnant (GD11-13) and non-pregnant rats.

Results: TK profiles of AS showed that the two groups of rats were similar after a single AS dose but were significantly different after multiple doses. Following a daily dose for 3 days, no change in AS concentration was found in the pregnant animals, but a significant concentration decline was seen in the non-pregnant rats on day 3. In addition, a higher conversion rate of AS to dihydroartemisinin (DHA) was detected in the pregnant rats after either single or multiple doses compared to non-pregnant controls. The ratios of AUC(DHA)/AUC(AS) were 0.99-1.02 for the pregnant rats and 0.42-0.48 for non-pregnant animals, resulting in a total AUC(DHA D1-3) that was about 3.7-fold higher in pregnant rats (15,049 ng.h/ml) than in non-pregnant rats (4,015 ng.h/ml). Furthermore, the tissue/blood partition coefficients demonstrated that the level of radiolabeled AS that was distributed into uterus, placenta, and ovary was 2-4-fold higher than in blood.

Conclusions: TK data showed that unchanged AS and DHA in the blood of pregnant rats were 1.53- and 3.74-fold, respectively, higher than those of non-pregnant animals, which all likely relate to the severe embryotoxicity of AS, even with a low-dosage regimen in pregnant animals.

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http://dx.doi.org/10.1002/bdrb.20164DOI Listing

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