INTERACTION OF DRUGS WITH P-GLYCOPROTEIN IN BRAIN CAPILLARIES

P-glycoprotein (P-gp) is expressed at high levels in a variety of non- cancerous tissues such as the endothelial cells of the blood-brain bar rier (BBB) capillaries. These thin capillaries tightly regulate the mo vement of substrates from the circulating blood into the brain. P-gp m ay be involved in the exclusion of various drugs from the capillary en dothelial cells, blocking their entry into the brain. However, interac tions of drugs with P-gp expressed in brain capillaries remain to be c haracterized. We have performed photoaffinity labeling studies using [ I-125]arylazidoprazosin (IAAP) to evaluate the inhibitory efficiency o f various compounds. Cyclosporin A (CsA) and its derivative PSC 833 (P SC) were the most effective inhibitors of IAAP binding among the drugs tested. The magnitude of inhibition was: PSC > CsA > quinidine > vinb lastine > verapamil > actinomycin D > colchicine > reserpine > bilirub in > doxorubicin > progesterone. Cremophor El, the vehicle used to adm inister CsA and PSC intravenously, was also able to inhibit IAAP photo labeling of P-gp. Labeling experiments were also performed using a pho toactivatable [H-3]CsA derivative. Photolabeling of P-gp with this com pound was abolished almost completely by CsA and PSC. In vivo studies were also performed by treating rats with CsA [10 mg/(kg . day) for 10 days]. Following this treatment, no alteration in the level of P-gp e xpression in brain capillaries was observed, These results suggest tha t, at the proper dosage, administration of CsA to cancer patients coul d help to enhance the response of brain tumors to chemotherapeutic age nts without modifying the intrinsic level of P-gp expression in this t issue.