Purpose

One function of the blood-brain barrier (BBB) is the efflux of xenobiotics by breast cancer resistance protein (BCRP), and inhibition of BCRP can cause unexpected central nervous system toxicity. Despite the importance of BCRP inhibition and the associated risk of BBB penetration in vivo, there has been little investigation of it to date. In this study, inhibition of BCRP-mediated transport was assessed by in vitro assay in the presence of bovine serum albumin (BSA) to change the unbound inhibitor concentrations, and the in vitro-in vivo correlation (IVIVC) at the BBB was evaluated.

Methods and Results

The IC₅₀ values of BCRP inhibitors were determined in vitro with and without BSA and the inhibitors were categorized into two groups. One group of compounds had little risk of inhibiting BCRP because of their low unbound concentrations. In contrast, the other group has the potential to facilitate BBB penetration by inhibiting BCRP. In the IVIVC approach, brain concentrations and the brain-to-plasma ratio were better correlated with the ratio of the unbound plasma concentration at steady-state to the unbound-fraction-adjusted IC₅₀.

Conclusion

We have found a way to obtain a better in vitro-in vivo correlation for BCRP-mediated transport.

中文翻译：

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通过使用未结合分数调整的 IC 50 来改善体外-体内相关性以抑制乳腺癌抗性蛋白

目的

血脑屏障 (BBB) 的一项功能是通过乳腺癌抗性蛋白 (BCRP) 排出异生物质，抑制 BCRP 会导致意想不到的中枢神经系统毒性。尽管 BCRP 抑制的重要性和 BBB在体内渗透的相关风险，但迄今为止对其的研究很少。在这项研究中，在牛血清白蛋白 (BSA) 存在下通过体外测定评估了 BCRP 介导的转运抑制，以改变未结合的抑制剂浓度，并评估 BBB 的体外-体内相关性 (IVIVC)。

方法和结果

BCRP 抑制剂的 IC ₅₀值在体外有无 BSA 时测定，抑制剂分为两组。一组化合物几乎没有抑制 BCRP 的风险，因为它们的未结合浓度很低。相比之下，另一组有可能通过抑制 BCRP 来促进 BBB 渗透。在 IVIVC 方法中，脑浓度和脑与血浆的比率与稳态未结合血浆浓度与未结合部分调整的 IC _{50 的}比率具有更好的相关性。

结论

我们已经找到了一种方法来获得BCRP 介导的转运的更好的体外-体内相关性。