Effect of bioflavonoids on vincristine transport across blood-brain barrier

Several grapefruit juice bioflavonoids, including quercetin, are reported to stimulate P-glycoprotein-mediated drug efflux from cultured tumor cells. To see whether these bioflavonoids alter the permeation of vincristine across the blood-brain barrier, we conducted experiments with cultured mouse brain capillary endothelial cells (MBEC4 cells) in vitro and ddY mice in vivo. The steady-state uptake of [H-3]vincristine by MBEC4 cells was decreased by 10 mu M quercetin, but increased by 50 mu M quercetin. Similarly, the in vivo brain-to-plasma concentration ratio of [H-3]vincristine in ddY mice was decreased by coadministration of 0.1 mg/kg quercetin, but increased by 1.0 mg/kg quercetin. Kaempferol had a similar biphasic effect on the in vitro uptake of [H-3]vincristine. Other aglycones tested (chrysin, flavon, hesperetin, naringenin) increased [H-3]vincristine uptake in the 10-50 mu M range, and glycosides (hesperidin, naringin, rutin) were without effect. We then addressed the mechanism of the concentration-dependent biphasic action of quercetin. Verapamil, a P-glycoprotein inhibitor, inhibited the efflux of [H-3]vincristine from MBEC4 cells, while 10 mu M quercetin significantly stimulated it. The uptake of [H-3]vincristine by MBEC4 cells was increased by inhibitors of protein kinase C, but decreased by phorbol 12-myristate-13-acetate (PMA), as well as by 10 mu M quercetin. The phosphorylation level of P-glycoprotein was increased in the presence of 5 mu M quercetin or 100 nM PMA, but decreased by the protein kinase C inhibitor H7 (1-(5-isoquinolinesulfonyl)-2-methyl-piperazine, 30 mu M). We conclude that low concentrations of quercetin indirectly activate the transport of [H-3]vincristine by enhancing the phosphorylation (and hence activity) of P-glycoprotein, whereas high concentrations of quercetin inhibit P-glycoprotein. Our results indicate that patients taking drugs which are P-glycoprotein substrates may need to restrict their intake of bioflavonoid-containing foods and beverages, such as grapefruit juice. (C) 2000 Elsevier Science B.V. All rights reserved.