Localization of artesunate and its derivatives in the pregnant rat and fetus following oral administration and relationship to developmental toxicity.
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.
Clark
Robert L
RL
Artemis Pharmaceutical Research, Lansdale, Pennsylvania 19446, USA. clarkrl33@hotmail.com
Gristwood
William E
WE
Lewsley
Richard
R
Wilson
Robert
R
Harrell
Andrew W
AW
D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D037621:Artemisinins / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D000077332:Artesunate; D001345:Autoradiography / Q000379:methods; D003622:Dapsone / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D005333:Fetus / Q000187:drug effects*; D008297:Male; D011247:Pregnancy; D002727:Proguanil / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D000962:Antimalarials; D037621:Artemisinins; D000077332:Artesunate; C039060:artenimol; C007030:chlorproguanil; D003622:Dapsone; D002727:Proguanil