Murine teratology and pharmacokinetics of the enantiomers of sodium 2-ethylhexanoate.
Murine teratology and pharmacokinetics of the enantiomers of sodium 2-ethylhexanoate.
复制标题
2-乙基己酸钠对映体的小鼠畸胎学和药代动力学。
DOI：
10.1016/0041-008x(92)90195-x
复制
发表时间：
1992
影响因子：
3.8
通讯作者：
Nau,H
中科院分区：
文献类型：
--
作者：
Collins,MD;Scott,WJ;Miller,SJ;Evans,DA;Nau,H
采用多次给药方案开发了（±）-2-乙基己酸钠诱导露脑畸形的小鼠模型。以半天间隔连续给药三次，诱导露脑畸形的最敏感时间为孕激素第8-9天。使用外消旋物质，确定SWV菌株比C57 BL 6 NCrlBR菌株对露脑畸形的诱导更敏感。通过制备型HPLC将2-乙基己酸的对映异构体分离至大于99.8%的光学纯度和根据气相色谱分析大于99%的纯度。研究表明，（R）-对映异构体是比（S）-对映异构体更有效的致畸剂，可诱导露脑畸形以及其他器官系统畸形。在母体血浆、母体肌肉和胚胎中对每种对映异构体进行药代动力学分析。药代动力学表明，三个隔室中两种对映体的峰浓度（Cmax）大致相等，并在第三次给药后15 min内达到。两种对映异构体的浓度-时间曲线下面积值比（R）-对映体高约10%，因为该化合物的消除略慢。生物样品中两种对映体的外消旋作用可忽略不计（或没有）。结果表明，畸形的差异，在2-乙基己酸钠的对映异构体不是由于这些对映体在胚胎中的浓度的差异，但更可能是由于特定的相互作用的对映异构体与手性分子在胚胎中。
A mouse model for the induction of exencephaly with sodium (±)-2-ethylhexanoate has been developed using multiple administration regimes. With three consecutive administrations at one-half-day intervals, the most sensitive time to induce exencephaly was Gestational Days 8–9. Using the racemic substance it was determined that the SWV strain was more sensitive to the induction of exencephaly than the C57BL 6NCrlBR strain. The enantiomers of 2-ethylhexanoic acid were separated via preparative HPLC to greater than 99.8% optical purity, and greater than 99% purity according to a gas chromatographic analysis. It was demonstrated that the (R)-enantiomer is a more potent teratogen than the (S)-enantiomer for the induction of exencephaly as well as malformations of other organ systems. Pharmacokinetic analyses for each of the enantiomers were performed in maternal plasma, maternal muscle, and embryo. The pharmacokinetics showed that the peak concentration (Cmax) for both enantiomers in the three compartments was approximately equivalent and was attained within 15 min following the third administration. The area under the concentration versus time curve values for the two enantiomers were approximately 10% higher for the (R)-antipode because of a slightly slower elimination of this compound. There was negligible (or no) racemization of the two enantiomers in the biological samples. The results suggest that teratologic differences in the enantiomers of sodium 2-ethylhexanoate are not due to differences in the concentrations of these antipodes in the embryo, but more likely result from the specific interaction of the enantiomers with chiral molecules in the embryo.