Ameltolide. II: Placental transfer of radiocarbon following the oral administration of a novel anticonvulsant in rats.
The placental transfer of orally administered ameltolide was evaluated to confirm embryonic exposure in the rat developmental toxicity study (Higdon et al., '91). Dissection techniques were used to determine the amount of total radiocarbon that traversed the placenta and distributed within the embryo in pregnant CD rats 0.75, 2, 5, 12, and 24 h after a single oral gavage dose of 50 mg/kg [14C]ameltolide on gestation day 12. Quantification of radiocarbon within placental and embryonic tissues and amniotic fluid was determined and compared with maternal plasma, liver, kidney, uterus, and ovary. Highest concentrations of radiocarbon occurred at 5 h postdose in all tissues sampled (maternal and embryonic) and then declined steadily over the 24-h time course of the study. Maternal liver contained the highest concentrations of radiocarbon at all time points and peaked at 5.86% of dose at 5 h. Embryonic tissues accounted for less than 0.2% of the administered dose at all time points. Tissue-to-maternal plasma ratios indicated that maternal liver and kidney concentrations were higher than maternal plasma concentrations at all time points. Uterine and ovarian concentrations were approximately equal to maternal plasma concentrations at 5, 12, and 24 h postdose. Although placental, embryonic, and amniotic fluid tissue-to-maternal plasma ratios were less than or equal to 1.0, ratios increased slightly throughout the time course of this study. Results from this study confirm embryonic exposure to radiocarbon associated with [14C]ameltolide and/or its metabolites in the rat developmental toxicity study, which has demonstrated the lack of observable teratogenic effects.
Pohland
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RC
Toxicology Research Laboratories, Eli Lilly and Company, Greenfield, Indiana 46140.
Vavrek
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MT
D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics*; D001549:Benzamides / Q000493:pharmacokinetics*; D002250:Carbon Radioisotopes; D005260:Female; D008431:Maternal-Fetal Exchange / Q000502:physiology*; D015394:Molecular Structure; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats
D000927:Anticonvulsants; D001549:Benzamides; D002250:Carbon Radioisotopes; C055323:ameltolide