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

Ziconotide is a selective peptide antagonist of the N-type calcium channel currently in clinical trials for analgesia. Ziconotide reached a maximal br ain 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 (syntheti c 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. injecti on, 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 d ialysis probes implanted into the hippocampus. Image analysis and serial se ctioning showed that diffusion of Ziconotide in the extracellular fluid aro und 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 micr ovessel endothelial cells (BBMEC) verified that a close structural analog o f Ziconotide (SNX-194) passed through this blood-brain barrier (BBB) model as expected for peptides of similar physical properties (permeability coeff icient 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 a mount of radioactivity was found to cross the BBB after perfusion of radioi odinated Ziconotide compared to [C-14]inulin. Capillary depletion experimen ts and HPT-C analysis defined the brain location and stability. (C) 2000 El sevier Science Inc. All rights reserved.