Contribution of P-glycoprotein to bunitrolol efflux across blood-brain barrier

In this study, we investigated the mechanism of the blood-brain barrier (BB B) transport of bunitrolol (BTL), as a model of beta-blocker, in vivo and i n vitro. In order to define the contribution of P-glycoprotein (P-gp) to th e active efflux of BTL from brain to blood, we examined the in vivo brain d istribution of BTL in mdr1a (-/-) mice with a disrupted mdr1a gene. After i ntravenous administration of BTL to mdr1a (-/-) mice, the brain concentrati on acid K-p value of BTL were significantly increased as compared with thos e in mdr1a (+/+) mice. Next, the contribution of the mdr1a P-gp to in vitro uptake of BTL was compared in LV500 cells and L cells (mouse mdr1a-express ing cells and host cells, respectively). The intracellular accumulations of [H-3]vinblastine and BTL by LV500 cells were lower than those by L cells, but were significantly increased by verapamil, a P-gp inhibitor. Furthermor e, the BTL uptake by KB-VJ300 cells, which express human P-gp, was also sig nificantly lower than that by KB host cells, and was increased by verapamil . The steady-state uptake of BTL by LLC-GA5-COL300 cells, expressing human P-gp, was significantly increased in the presence of 20 mu M cyclosporin A (another P-gp inhibitor), which had no effect in the LLC-PK1 host cells. On the other hand, the steady-state intracellular accumulation of BTL by MBEC 4 cells, which express mdr1b P-gp instead of mdr1a P-gp, was not significan tly changed in the presence of verapamil. This finding suggested that BTL i s not a good substrate for mdr1b P-gp. In conclusion, our results suggest t hat BTL is transported from brain to blood by mdr1a P-gp in mice and by MDR 1 in humans, and this presumably accounts for the low brain distribution of BTL. Copyright (C) 1999 John Wiley & Sons, Ltd.