The dynamics of intrathecal bolus and cerebrospinal solute transport

1555 Objectives The goals of our studies was to investigate the dynamics of in vivo transport of solutes administered to the CSF, evaluate the relevance of rodent models for intrathecal drug transport studies, and to develop methodologies for fully quantitative non-invasive studies of solute dynamics in the CSF. Methods Recombinant human enzymes, soluble polymers and nanoparticles were labeled with 124I or 89Zr and administered IT to rats and cynomolgus monkeys. Studies were carried out by PET. Dynamic imaging data (0-30 min post injection) and multiple whole-body images (over at least 48 hours) were acquired. Images were analyzed to determine the rates and patterns of the label spread in the CSF from the injection site. Results The initial solute distribution in the CSF greatly depended on the injected volume. Solutes injected in high volume translocate to cervical/basal cerebral area. In non-human primates, lumbar administration at 0.5 ml/kg resulted in the immediate delivery of >50% of the injected volume to the cerebral CSF. No evidence of directional solute flows anywhere in the CSF was found. Solute penetration into both white and gray matter from the CSF was found by 5 hours after the injection and confirmed by microscopy data. Systemic presence of the solutes was detected early after the injection. The data suggests size-dependent direct drainage from the CSF to the blood through the arachnoid granulations. No evidence of lymphatic drainage of CSF was found in monkeys in any region; in rats drainage was detected in deep anterior cervical area. The general patterns of solute transport in the CSF of rodents and monkeys were similar. Conclusions Hydrostatic compliance is the major factor of the initial distribution of the administered solute in the CSF compartment. CSF hydrodynamics plays the major role in the subsequent fast (head) and slow (spine) solute redistribution in the CSF. Rodent models are relevant and potentially scalable. Research Support NOH, DoD, Synageva Biopharma, Shire Inc., Neurophage Pharmaceuticals