Oral absorption and in vivo biodistribution of α-conotoxin MII and a lipidic analogue
Oral absorption and in vivo biodistribution of α-conotoxin MII and a lipidic analogue
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DOI：
10.1016/j.bbrc.2007.06.138
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发表时间：
2007-09-14
影响因子：
3.1
通讯作者：
Toth, Istvan
中科院分区：
文献类型：
--
作者：
Blanchfield, Joanne T.;Gallagher, Oliver P.;Toth, Istvan
芋螺毒素是高度受限的肽毒素，具有药学相关的生物活性。我们在此报道了雄性斯普拉格-道利大鼠静脉内 (iv) 和口服给药后天然 α-芋螺毒素、MII 和 MII 的亲脂性类似物 (N-LaaMII) 的吸收程度和分布情况。 N-LaaMII 是通过将 2-氨基-D,L-十二烷酸 (Laa) 偶联到 MII 的 N 末端而形成的，之前已被证明与天然 MII 相比，在 Caco-2 细胞单层中的渗透性显着提高，同时保持了母肽的 nAChR 抑制效力。口服给药后，两种肽均穿过胃肠道（30 m 后穿过胃肠道的比例接近 6%）。虽然 Laa 结合并没有显着改善吸收，但静脉注射后确实大大增加了化合物在肝脏中的积累。这两种肽都没有显着程度地穿过血脑屏障。这是首次对口服后α-芋螺毒素的体内生物分布进行研究。 (c) 2007 Elsevier Inc. 保留所有权利。
Conotoxins are highly constrained peptide toxins that exhibit pharmaceutically relevant biological activities. We herein report the extent of absorption and profile of distribution of a native alpha-conotoxin, MII and a lipophilic analogue of MII (N-LaaMII) after intravenous (iv) and oral administration to male Sprague-Dawley rats. N-LaaMII is formed by coupling 2-amino-D,L-dodecanoic acid (Laa) to the N-terminus of MII and has previously been shown to exhibit significantly improved permeability across Caco-2 cell monolayers compared to the native MII while maintaining the potency in inhibition of nAChRs of the parent peptide. Both peptides crossed the GI tract after oral administration (similar to 6% after 30 m). While Laa conjugation did not significantly improve absorption, it did greatly increase the accumulation of the compound in the liver after iv administration. Neither peptide crossed the blood-brain barrier to any significant extent. This is the first study of the in vivo biodistribution of an alpha-conotoxin after oral administration. (c) 2007 Elsevier Inc. All rights reserved.