Intra-arterial mitoxantrone delivery in rabbits: an optical pharmacokinetic study.

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.