DOSE-DEPENDENT DELIVERY OF COLCHICINE TO THE RAT HIPPOCAMPUS BY MICRODIALYSIS

The time courses of the colchicine delivery and diffusion rate in the brain were studied by microdialysis in the rat. Microdialysis allowed the exposure of the brain tissue to colchicine to be regulated, unlike a bolus injection. Colchicine was infused directly into the dorsal hi ppocampus at 40 ng/ml and 40 mu g/ml, for 8 h. The amount of colchicin e delivered to the brain and the diffusion rate from the probe were do se-dependent: colchicine diffusion into the brain was linear at 40 ng/ ml but tended to plateau after 4 h at 40 mu g/ml. The drug actually de livered with the higher dosage was only about 50% of that predicted fr om a constant diffusion. The total amount delivered at 40 ng/ml was 3. 73 +/- 0.14 ng and at 40 mu g/ml, it was 2.06 +/- 0.20 mu g. Thus tiss ues surrounding the infusion site were saturated at high concentration and no more colchicine was diffused. Postmortem measurements of colch icine concentration in the forebrain confirmed these findings. Hence, the way in which colchicine is delivered to the brain is a critical fa ctor for induction of its neurotoxic effects. These data open the way to a research on the correlation between local brain concentrations of colchicine and neurodegenerescence.