Bioavailability of Ziconotide in brain: influx from blood, stability, and diffusion
Bioavailability of Ziconotide in brain: influx from blood, stability, and diffusion
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DOI：
10.1016/s0196-9781(00)00175-3
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发表时间：
2000-04-01
期刊：
影响因子：
3
通讯作者：
Miljanich, G
中科院分区：
文献类型：
--
作者：
Newcomb, R;Abbruscato, TJ;Miljanich, G
齐康肽是一种N型钙通道的选择性多肽拮抗剂，目前正在进行临床镇痛试验。在静脉注射后3-20分钟，每克组织中的最大脑浓度达到注射物质的0.003-0.006%。静脉注射后2小时降至0.001%/g以下，结构明显不同的海参多肽SNX-185(合成的TVIA)静脉注射后在脑内的存留显著增加。给药，0.0035%的注射物质在静脉注射后2-4小时出现。当将这些多肽通过体内植入海马区的透析探针灌流时，也得到了类似的结果(即SNX185的持久性更强)。图像分析和连续切片显示，在透析探针周围的胞外液中扩散很小，2 h后，肽位于探针周围1 mm的范围内。体外通过培养的牛脑微血管内皮细胞(BBMEC)的扩散证实，与物理性质相似的多肽(渗透系数为6.5×10(-4)cm/g)一样，结构上接近的齐康肽(SNX-194)可以通过这个血脑屏障(BBB)模型。从血液到脑的通道也通过颈动脉的原位灌流得到证实。与[C-14]菊粉相比，在灌流放射性碘化齐康肽后，发现穿过血脑屏障的放射性在统计学上更大。毛细血管耗竭实验和HPT-C分析确定了脑的位置和稳定性。(C)2000 Elsevier Science Inc.保留所有权利。
Ziconotide is a selective peptide antagonist of the N-type calcium channel currently in clinical trials for analgesia. Ziconotide reached a maximal brain concentration of between 0.003 and 0.006% of the injected material per gram of tissue at 3-20 min after i.v. injection, and this decayed to below 0.001%/g after 2 h. The structurally distinct conopeptide SNX-185 (synthetic TVIA) was considerably more persistent in brain after i.v. administration, with 0.0035% of the injected material present at 2-4 h after i.v. injection, and 0.0015% present at 24 h. Similar results (i.e, greater persistence of SNX-185) were obtained when the peptides were perfused through in vivo dialysis probes implanted into the hippocampus. Image analysis and serial sectioning showed that diffusion of Ziconotide in the extracellular fluid around the dialysis probe was minimal, with the peptide located within 1 mm of the probe after 2 h. In vitro diffusion through cultured bovine brain microvessel endothelial cells (BBMEC) verified that a close structural analog of Ziconotide (SNX-194) passed through this blood-brain barrier (BBB) model as expected for peptides of similar physical properties (permeability coefficient of 6.5 x 10(-4) cm/g). Passage from blood to brain was also verified by in situ perfusion through the carotid artery. A statistically greater amount of radioactivity was found to cross the BBB after perfusion of radioiodinated Ziconotide compared to [C-14]inulin. Capillary depletion experiments and HPT-C analysis defined the brain location and stability. (C) 2000 Elsevier Science Inc. All rights reserved.