Role of P-170 glycoprotein in colchicine brain uptake.

To study the role of P-glycoprotein (P-gp) in the delivery of colchicine from blood to brain, the pharmacokinetics of colchicine in plasma and brain was studied in the rat by an in vivo method and by the in situ brain perfusion technique. Colchicine was administered intravenously at three doses (1, 2.5, and 5 mg/kg) with or without an inhibitor of P-gp, verapamil (0.5 mg/kg i.v.); blood and brain samples were taken at t = 1, 2, and 3 hr. Areas under the colchicine curve at doses from 2.5 to 5 mg/kg were proportional to dose for plasma but not for brain. At a colchicine dose of 5 mg/kg, verapamil co-treated rats showed a 1.65-fold enhancement of the colchicine concentration in plasma but a 4.5-fold enhancement in brain. During short experimental times (in situ brain perfusion technique), a comparable enhancement was found (4.26-fold): mean distribution volumes of colchicine were enhanced from 0.23 +/- 0.17 to 0.98 +/- 0.19 microl/g for the eight gray areas, and no effect was observed in the choroid plexus, which do not express P-gp. These results clearly show that P-gp, present at the luminal surface of the capillary endothelial cells, is responsible for the weak penetration of colchicine into the brain.