Abstract
BACKGROUND: Several human studies have demonstrated the feasibility of intra-arterial delivery of mitoxantrone in systemic malignancies. Computational models predict that an intra-arterial bolus injection of mitoxantrone during transient cerebral hypoperfusion will enhance brain tissue drug deposition in comparison with injections during normal blood flow. OBJECTIVE: To assess whether transient reduction in cerebral blood flow would enhance the delivery of mitoxantrone. This is accomplished by obtaining real-time measurements of mitoxantrone concentrations in brain tissues by using a novel optical pharmacokinetics technique, based on reflectance spectroscopy. METHODS: The blood-brain barrier of anesthetized rabbits was disrupted by intracarotid injection of mannitol (8 mL, 25% over 40 seconds). Thereafter, animals received 3 mg of mitoxantrone injection during normal perfusion (n = 5) or cerebral hypoperfusion that was induced by contralateral arterial occlusion and systemic hypotension (n = 8). RESULTS: Cerebral hypoperfusion significantly decreased the cerebral blood flow, allowing a longer exposure time of the drug. It was determined that therapeutic concentrations of mitoxantrone were achieved in both groups; however, hypoperfusion did not increase the tissue concentrations of mitoxantrone after 20 minutes. CONCLUSION: These results demonstrate the effective delivery of mitoxantrone by the intra-arterial route, after blood-brain-barrier disruption, but the predicted benefits of flow reduction for improving intra-arterial deposition of mitoxantrone was not evident.