Division of Pharmaceutics, Osaka University of Pharmaceutical Sciences, Japan.
Biol Pharm Bull. 2011;34(8):1246-51. doi: 10.1248/bpb.34.1246.
Furanocoumarin derivatives, known as components of grapefruit juice, showing inhibitory effects against P-glycoprotein (P-gp) in the intestine are also contained in the plants of rutaceae and umbelliferae families, which are used as components of Kampo extract medicines. In this study, we investigated the inhibitory effects of byakangelicol and rivulobirin A, known as furanocoumarins showing P-gp inhibitory effect using Caco-2 monolayer, against P-gp at the blood-brain barrier (BBB) under both in vitro and in vivo conditions. First we studied the membrane permeability of furanocoumarins to clarify whether they can be absorbed from the intestine. Both furanocoumarins showed high permeability through the Caco-2 monolayer, suggesting that they can easily reach the systemic circulation after oral administration. Then, we evaluated the effect of these furanocoumarins on the uptake of calcein acetoxymethyl ester (calcein-AM), a P-gp substrate, into bovine brain microvascular endothelial cells (BBMEC). Both furanocoumarins significantly increased the uptake amount of calcein-AM into BBMEC by the inhibition of P-gp at the BBB in vitro. Next we also investigated the P-gp inhibitory effect of these furanocoumarins at the rat BBB in vivo using verapamil as a P-gp substrate. Both furanocoumarins increased the B/P ratio of verapamil compared to the control, even under in vivo conditions; however, the extent of the inhibitory effect was much lower than in vitro condition. In conclusion, byakangelicol and rivulobirin A may inhibit P-gp expressed at the BBB even under in vivo conditions. Further studies using Kampo extract medicines under in vivo condition are necessary for safe drug therapy.
呋喃香豆素衍生物是葡萄柚汁中的成分，对肠道中的 P-糖蛋白（P-gp）具有抑制作用，它们也存在于芸香科和伞形科植物中，这些植物是汉方药提取物的成分。在这项研究中，我们使用 Caco-2 单层细胞研究了已知具有 P-gp 抑制作用的呋喃香豆素毕当归醇和瑞枯灵 A 对体外和体内血脑屏障（BBB）中 P-gp 的抑制作用。首先，我们研究了呋喃香豆素的膜通透性，以阐明它们是否可以从肠道吸收。这两种呋喃香豆素均通过 Caco-2 单层具有高通透性，表明它们在口服后很容易到达体循环。然后，我们评估了这些呋喃香豆素对 calcein 乙酰氧甲基酯（calcein-AM）摄取的影响，calcein-AM 是 P-gp 的底物，进入牛脑微血管内皮细胞（BBMEC）。这两种呋喃香豆素在体外均显著抑制 BBB 中的 P-gp，从而增加了 calcein-AM 进入 BBMEC 的摄取量。接下来，我们还使用维拉帕米作为 P-gp 底物，在体内研究了这些呋喃香豆素对大鼠 BBB 中 P-gp 的抑制作用。与对照组相比，这两种呋喃香豆素均增加了维拉帕米的 B/P 比值，即使在体内条件下也是如此；然而，抑制作用的程度远低于体外条件。总之，毕当归醇和瑞枯灵 A 即使在体内条件下也可能抑制 BBB 中表达的 P-gp。在体内条件下使用汉方药提取物进行进一步的研究对于安全的药物治疗是必要的。
