Oral absorption and in vivo biodistribution of α-conotoxin MII and a lipidic analogue

被引:25
作者
Blanchfield, Joanne T.
Gallagher, Oliver P.
Cros, Cecile
Lewis, Richard J.
Alewood, Paul F.
Toth, Istvan [1 ]
机构
[1] Univ Queensland, Sch Mol & Microbial Sci, Brisbane, Qld 4072, Australia
[2] Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia
关键词
alpha-conotoxin MII; alpha-aminododecanoic; biodistribution; lipoamino acid; oral absorption; 3-DIMENSIONAL SOLUTION STRUCTURE; REVERSIBLE LIPIDIZATION; CONUS PEPTIDES; DELIVERY; PROBES; BRAIN; DRUGS; BLOOD;
D O I
10.1016/j.bbrc.2007.06.138
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:97 / 102
页数:6
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