NDLI: Localization of artesunate and its derivatives in the pregnant rat and fetus following oral administration and relationship to developmental toxicity.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Clark, Robert L. Gristwood, William E. Lewsley, Richard Wilson, Robert Harrell, Andrew W.
Description	Country affiliation: United States Author Affiliation: Clark RL ( Artemis Pharmaceutical Research, Lansdale, Pennsylvania 19446, USA. clarkrl33@hotmail.com)
Abstract	BACKGROUND: The antimalarial drug artesunate affects erythroid cells leading to developmental toxicity and adult reticulocytopenia. We report on a kinetic study in rats and the tissue distribution of radioactivity following oral administration of [(3)H]-artesunate to pregnant rats using quantitative whole-body autoradiography (QWBA). METHODS: Rats were dosed orally with chlorproguanil/dapsone/artesunate (including 11.8 mg/kg artesunate) and plasma concentrations of artesunate and the active metabolite dihydroartemisinin (DHA) were determined. In the QWBA study, 6 rats received 13 mg/kg [(3)H]-artesunate on day 18 of gestation. Groups of 2 rats were euthanized at 1, 6, and 24 hours after dosing, rapidly frozen, and sectioned in a cryostat. Sagittal sections were freeze-dried and placed in contact with imaging plates. Tissue concentrations of radioactivity were quantified. RESULTS: Systemic exposure to DHA was up to 22-fold higher than the parent compound and was higher in non-pregnant females than males. In the QWBA study, high concentrations of radioactivity were seen in maternal tissues involved in absorption and excretion, the bone marrow and spleen. Fetal blood and liver levels were 3.8- to 8.8-fold higher than maternal blood levels at all timepoints. CONCLUSIONS: Excluding tissues involved in absorption and excretion, the highest concentrations of radioactivity were observed in tissues involved in hemoglobin synthesis and/or destruction in both the mother and the fetus and likely account for the maternal reticulocytopenia and embryotoxicity. Radioactivity concentrations in the fetal blood were 2.1- to 2.8-fold higher than maternal bone marrow at all timepoints and this difference could contribute to the lower dose threshold for embryotoxicity.
File Format	HTM / HTML
ISSN	15429733
Issue Number	5
Volume Number	89
e-ISSN	15429741
Journal	Birth Defects Research Part B: Developmental and Reproductive Toxicology
Language	English
Publisher	Wiley
Publisher Date	2010-10-01
Publisher Place	United States
Access Restriction	Subscribed
Subject Keyword	Discipline Teratology Discipline Toxicology Antimalarials Pharmacokinetics Toxicity Artemisinins Fetus Drug Effects Administration, Oral Animals Administration & Dosage Blood Autoradiography Methods Dapsone Female Male Pregnancy Proguanil Analogs & Derivatives Random Allocation Rats Rats, Sprague-dawley Tissue Distribution Journal Article
Content Type	Text
Resource Type	Article
Subject	Developmental Biology Health, Toxicology and Mutagenesis Toxicology Embryology

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