Pharmacokinetic determinants of embryotoxicity in rats associated with organic acids.
Pharmacokinetic determinants of embryotoxicity in rats associated with organic acids.
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DOI：
10.1289/ehp.94102s1197
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发表时间：
1994-12
影响因子：
10.4
通讯作者：
Nau H
中科院分区：
文献类型：
--
作者：
Scott WJ Jr;Collins MD;Nau H
我们研究了四种结构相似的有机酸，以进一步了解其发育毒性的基础。丙戊酸（2-丙基戊酸）、乙基己酸和辛酸是同分异构的C8有机酸，但它们的致畸效力差异很大。在大鼠妊娠第12天单次经口给予6.25 mmol/kg丙戊酸后，可诱导中度至重度畸形结局。两倍的乙基己酸（12.5 mmol/kg）诱导的反应不太严重。辛酸即使在18.75 mmol/kg的极高剂量下也无致畸性。后一结果无疑是由于辛酸的肠道吸收不良，因为母体血浆水平从未达到丙戊酸和乙基己酸测量值的一半。此外，母体血浆中只有一小部分真正转移到胚胎中。另一方面，丙戊酸和乙基己酸的峰浓度和暴露持续时间非常相似，尽管丙戊酸给药后的畸形结局更严重，这表明后者的内在活性更高。还研究了第四种试剂甲基己酸，当以14.1 mmol/kg给药时，没有致畸作用。该药物的药代动力学研究显示，母体血浆和胚胎中的峰浓度高于丙戊酸或乙基己酸，但暴露持续时间较短。我们的结论是，药代动力学参数可以是致畸结果的重要决定因素，从而有助于解释不同的结构相似的化学品的效力。
We have studied four organic acids of similar structure to further understand the basis of their developmental toxicity. Valproic acid (2-propyl pentanoic acid), ethylhexanoic acid, and octanoic acid are isomeric C8 organic acids but their teratologic potency varied widely. Valproic acid induced a moderate to severe teratologic outcome after a single oral administration of 6.25 mmoles/kg on day 12 of rat pregnancy. Twice as much ethylhexanoic acid (12.5 mmoles/kg) induced a less severe response. Octanoic acid was nonteratogenic even at the very high dose of 18.75 mmoles/kg. This latter result is undoubtedly due to poor intestinal absorption of octanoic acid, as the maternal plasma levels never reached half of those measured for valproic acid and ethylhexanoic acid. Moreover, only a tiny fraction of that in maternal plasma was actually transferred into the embryo. On the other hand, the peak concentration and duration of exposure to valproic acid and ethylhexanoic acid were very similar despite a more severe teratologic outcome following valproic acid, which indicated higher intrinsic activity of this latter agent. A fourth agent, methylhexanoic acid, was also studied and had no teratogenic effects when given at 14.1 mmoles/kg. Pharmacokinetic studies of this agent revealed higher peak concentrations in maternal plasma and embryo than valproic acid or ethylhexanoic acid, but the duration of exposure was shorter. We conclude that pharmacokinetic parameters can be important determinants of teratologic outcome and thereby help explain differing potencies of structurally similar chemicals.