Bioavailability of Ziconotide in brain: Influx from blood, stability, and diffusion

Robert Newcomb, Thomas J. Abbruscato, Tej Singh, Laszlo Nadasdi, Thomas P. Davis, George Miljanich

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

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 [14C]inulin. Capillary depletion experiments and HPLC analysis defined the brain location and stability. Copyright (C) 2000 Elsevier Science Inc.

Original languageEnglish (US)
Pages (from-to)491-501
Number of pages11
JournalPeptides
Volume21
Issue number4
DOIs
StatePublished - Apr 1 2000

Keywords

  • Blood-brain barrier
  • In vivo dialysis
  • MVII-A
  • Omega-conopeptide
  • SNX-111
  • Ziconotide

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Endocrinology
  • Cellular and Molecular Neuroscience

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    Newcomb, R., Abbruscato, T. J., Singh, T., Nadasdi, L., Davis, T. P., & Miljanich, G. (2000). Bioavailability of Ziconotide in brain: Influx from blood, stability, and diffusion. Peptides, 21(4), 491-501. https://doi.org/10.1016/S0196-9781(00)00175-3