ROLE OF P-GLYCOPROTEIN IN THE BLOOD-BRAIN TRANSPORT OF COLCHICINE ANDVINBLASTINE

Classically, drug penetration through the blood-brain barrier depends on the lipid solubility of the substance, except for some highly lipop hilic drugs, like colchicine and vinblastine, both substrates of P-gly coprotein, a drug efflux pump present at the luminal surface of the br ain capillary endothelial cells. Colchicine and vinblastine uptake int o the brain was studied in the rat using the in situ brain perfusion t echnique and two inhibitors of P-glycoprotein, verapamil and SDZ PSC-8 33. When rats were pretreated with PSC-833 (10 mg/kg, intravenous bolu s), colchicine and vinblastine uptake was enhanced 8.42- and 9.08-fold , respectively, in all the gray areas of the rat brain studied. The me an colchicine distribution volume was increased from 0.67 +/- 0.41 to 5.64 +/- 0.70 mu l/g and vinblastine distribution volume from 2.74 +/- 1.15 to 24.88 +/- 4.03 mu l/g. When rats were pretreated with verapam il (1 mg/kg, intravenous bolus), colchicine distribution volume was in creased 3.70-fold. The increase in colchicine and vinblastine did not differ between the eight brain gray areas. PSC-833 and verapamil pretr eatment had no influence on the distribution volume of either drug in the choroid plexus. Nevertheless, distribution volumes remained small, considering the highly lipophilic nature of the substances. We sugges t that P-glycoprotein is either only partially inhibited (difficulty o f fully saturating P-glycoprotein, especially under in vivo conditions ) or not the only barrier to these two drugs.