The potential inhibitory effect of antiparasitic drugs and natural products on P-glycoprotein mediated efflux
The potential inhibitory effect of antiparasitic drugs and natural products on P-glycoprotein mediated efflux
复制标题
DOI：
10.1016/j.ejps.2006.05.009
复制
发表时间：
2006-09-01
影响因子：
4.6
通讯作者：
Ungell, Anna-Lena B.
中科院分区：
文献类型：
--
作者：
Hayeshi, Rose;Masimirembwa, Collen;Ungell, Anna-Lena B.
研究了抗寄生虫药物和天然化合物对p -糖蛋白（Pgp）的潜在抑制作用。通过抑制Pgp介导的[H-3]-紫杉醇在Caco-2细胞中的转运，筛选Pgp相互作用的化合物。通过Caco-2细胞进一步评估选定抑制剂的双向转运，以确定潜在的Pgp底物。21种抗寄生虫药中，有14种对Pgp介导的[3H]-紫杉醇具有抑制作用，K-iapp值在4 ~ 2000 μ m之间，其中抗疟药物奎宁的抑制作用最强，K（iapp）值为4 μ m。12种天然化合物中，有3种对[H-3]-紫杉醇转运具有抑制作用，K-iapp值在50 ~ 400 μ m之间。进一步研究槲皮素和噻苯达唑的双向转运实验，以确定它们是否为Pgp的底物。奎宁在分泌方向上的转运超过了在吸收方向上的转运，并且是饱和的，表明奎宁是一种Pgp底物。其余抑制PgP的化合物没有显示出PgP底物的证据。总之，我们已经证明了大量的抗寄生虫和天然化合物，在一定浓度范围内，能够抑制Pgp介导的[H-3]-紫杉醇在Caco-2细胞中的外排，而不作为底物，这可能与Pgp的药物相互作用有关。(c) 2006 Elsevier B.V.版权所有
The potential inhibitory effect on P-glycoprotein (Pgp) by antiparasitic drugs and natural compounds was investigated. Compounds were screened for Pgp interaction based on inhibition of Pgp mediated [H-3]-taxol transport in Caco-2 cells. Bidirectional transport of selected inhibitors was further evaluated to identify potential Pgp substrates using the Caco-2 cells. Of 21 antiparasitics tested, 14 were found to inhibit Pgp mediated [3H]-taxol with K-iapp values in the range 4-2000 mu M. The antimalarial quinine was the most potent inhibitor with a K(iapp)of 4 mu M. Of the 12 natural compounds tested, 3 inhibited [H-3]-taxol transport with K-iapp values in the range 50-400 mu M. Quinine, amodiaquine, chloroquine, flavone, genistein, praziquantel, quercetin and thiabendazole were further investigated in bidirectional transport assays to determine whether they were substrates for Pgp. Transport of quinine in the secretory direction exceeded that in the absorptive direction and was saturable, suggesting quinine being a Pgp substrate. The rest of the compounds inhibiting PgP showed no evidence of being Pgp substrates. In conclusion, we have demonstrated that a substantial number of antiparasitic and natural compounds, in a range of concentrations, are capable of inhibiting Pgp mediated [H-3]-taxol efflux in Caco-2 cells, without being substrates and this may have implications for drug interactions with Pgp. (c) 2006 Elsevier B.V. All rights reserved.