Characterization of P-Glycoprotein Inhibitors for Evaluating the Effect of P-Glycoprotein on the Intestinal Absorption of Drugs.
Characterization of P-Glycoprotein Inhibitors for Evaluating the Effect of P-Glycoprotein on the Intestinal Absorption of Drugs.
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DOI：
10.3390/pharmaceutics13030388
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发表时间：
2021-03-15
期刊：
影响因子：
5.4
通讯作者：
Fujita T
中科院分区：
文献类型：
--
作者：
Kono Y;Kawahara I;Shinozaki K;Nomura I;Marutani H;Yamamoto A;Fujita T
为了开发口服药物，准确预测新化学物质的口服吸收是非常必要的。然而，由于包括P-糖蛋白(P-gp)在内的外排转运体参与了它们的吸收过程，这是很困难的。本研究比较分析了7种P-gp抑制剂(环孢菌素A、GF120918、LY335979、XR9576、WK-X-34、VX-710和OC144-093)对药物吸收的抑制作用。GF120918、LY335979和XR9576显著降低了P-gp底物紫杉醇通过Caco-2细胞单层的基底端到顶端的转运。GF120918还抑制了乳腺癌耐药蛋白(BCRP)底物米托蒽酮在Caco-2细胞中从底部到顶端的转运，而LY335979几乎不影响米托蒽酮的转运。此外，LY335979可显著提高野生型小鼠口服紫杉醇的吸收速率，与mdr1a/1b基因敲除小鼠相似。此外，野生型小鼠经LY335979处理后，BCRP底物拓扑替康的吸收速率与mdr1a/1b基因敲除小鼠相似，但显著低于BCRP基因敲除小鼠。这些结果表明，LY335979对P-gp具有选择性抑制活性，可用于评价P-gp对药物吸收的贡献。
For developing oral drugs, it is necessary to predict the oral absorption of new chemical entities accurately. However, it is difficult because of the involvement of efflux transporters, including P-glycoprotein (P-gp), in their absorption process. In this study, we conducted a comparative analysis on the inhibitory activities of seven P-gp inhibitors (cyclosporin A, GF120918, LY335979, XR9576, WK-X-34, VX-710, and OC144-093) to evaluate the effect of P-gp on drug absorption. GF120918, LY335979, and XR9576 significantly decreased the basal-to-apical transport of paclitaxel, a P-gp substrate, across Caco-2 cell monolayers. GF120918 also inhibited the basal-to-apical transport of mitoxantrone, a breast cancer resistance protein (BCRP) substrate, in Caco-2 cells, whereas LY335979 hardly affected the mitoxantrone transport. In addition, the absorption rate of paclitaxel after oral administration in wild-type mice was significantly increased by pretreatment with LY335979, and it was similar to that in mdr1a/1b knockout mice. Moreover, the absorption rate of topotecan, a BCRP substrate, in wild-type mice pretreated with LY335979 was similar to that in mdr1a/1b knockout mice but significantly lower than that in bcrp knockout mice. These results indicate that LY335979 has a selective inhibitory activity for P-gp, and would be useful for evaluating the contribution of P-gp to drug absorption.
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