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

✍ Scribed by Jo Matsuzaki; Chika Yamamoto; Tetsuo Miyama; Hitomi Takanaga; Hirotami Matsuo; Hitoshi Ishizuka; Yukinori Kawahara; Michihiko Kuwano; Mikihiko Naito; Takashi Tsuruo; Yasufumi Sawada

• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 143 KB
• Volume: 20
• Category: Article
• ISSN: 0142-2782
• DOI: 10.1002/(sici)1099-081x(199903)20:2<85::aid-bdd159>3.0.co;2-3

✦ Synopsis

In this study, we investigated the mechanism of the blood -brain barrier (BBB) transport of bunitrolol (BTL), as a model of i-blocker, in vivo and in vitro. In order to define the contribution of P-glycoprotein (P-gp) to the active efflux of BTL from brain to blood, we examined the in vivo brain distribution of BTL in mdr1a( -/-) mice with a disrupted mdr1a gene. After intravenous administration of BTL to mdr1a( -/-) mice, the brain concentration and K p value of BTL were significantly increased as compared with those 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-expressing cells and host cells, respectively). The intracellular accumulations of [ 3 H]vinblastine and BTL by LV500 cells were lower than those by L cells, but were significantly increased by verapamil, a P-gp inhibitor. Furthermore, the BTL uptake by KB-VJ300 cells, which express human P-gp, was also significantly 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 vM 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 MBEC4 cells, which express mdr1b P-gp instead of mdr1a P-gp, was not significantly changed in the presence of verapamil. This finding suggested that BTL is not a good substrate for mdr1b P-gp. In conclusion, our results suggest that BTL is transported from brain to blood by mdr1a P-gp in mice and by MDR1 in humans, and this presumably accounts for the low brain distribution of BTL.