Severe embryolethality of artesunate related to pharmacokinetics following intravenous and intramuscular doses in pregnant rats.
Artesunate (AS), a rapid, effective, and safe antimalarial drug, has been used for the treatment of malaria for decades. However, severe embryolethality was found for injectable AS in pregnant animals. In the present study, pregnant rats were selected and dosed with AS (GMP product) intravenously (IV) and intramuscularly (IM) at varied doses daily for 13 days from gestation day (GD) 6 to 18. In addition, a toxic dose of 1.2 mg/kg/day was subsequently tested in the GD 6-10, GD 11-15, and GD 16-20 periods of rat pregnancy. A pharmacokinetic study was also conducted to evaluate the bioavailability of AS following the IM administrations. Results showed that no significant adverse effects were found in maternal rats. All of the fetuses were either damaged or reabsorbed by placentas in treated pregnant rats, but doses did not show an adverse effect at 0.4 and 0.5 mg/kg after IV and IM administrations, respectively. The survival rate of fetuses is dose-dependent and the 50% fetus re-absorption doses (FRD(50)) were 0.61 and 0.60 mg/kg following the IV and IM, respectively. The most drug-sensitive period, showing severe embryotoxicity, was between GD 11 and 15 for injectable AS. When calculated with total concentrations of AS and dihydroartemisinin, an active metabolite of AS, the bioavailability of 97.8% after intramuscular injection was fulfilled to a bioequivalence of that in intravenous treatment. The fact that injectable AS exhibited severe embryolethality after both IV and IM injections seems related to their comparable pharmacokinetic profiles that indicate high peak concentrations in pregnant animals.
Li
Qigui
Q
Department of Pharmacology, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland 20307-5100, USA. qigui.li@us.army.mil
Si
Yuanzheng
Y
Xie
Lisa
L
Zhang
Jing
J
Weina
Peter
P
D000818:Animals; D000962:Antimalarials / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D037621:Artemisinins / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D000077332:Artesunate; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D020964:Embryo Loss / Q000139:chemically induced* / Q000378:metabolism; D004622:Embryo, Mammalian / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005327:Fetal Resorption / Q000139:chemically induced* / Q000378:metabolism; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization; D013997:Time Factors
D000962:Antimalarials; D037621:Artemisinins; D000077332:Artesunate