Effect of Pluronic P123 and F127 Block Copolymer on P-glycoprotein Transport and CYP3A Metabolism
Effect of Pluronic P123 and F127 Block Copolymer on P-glycoprotein Transport and CYP3A Metabolism
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DOI：
10.1007/s12272-011-1016-0
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发表时间：
2011-10-01
影响因子：
6.7
通讯作者：
Li, Gao
中科院分区：
文献类型：
--
作者：
Guan, Yanbin;Huang, Jiangeng;Li, Gao
本研究旨在评价pluronic P123 （P123）和pluronic F127 （F127）分别以罗丹明-123 （R-123）和咪达唑仑为底物对肠道p -糖蛋白（P-gp）和细胞色素P450 3A的影响。以Caco-2细胞和外翻肠囊作为肠粘膜模型，评估R-123的肠道吸收，以大鼠肠微粒体研究P123和F127对咪达唑仑体外代谢的影响。P123和F127以剂量依赖的方式增加Caco-2细胞内R-123的积累。P123显著降低了两种浓度下Caco-2单层中R-123的外排比，而F127仅降低了1%的外排比。此外，两种pluronics均能显著增强大鼠切除回肠黏膜对R-123的浆膜吸收。然而，无论P123和F127的浓度如何，P123或F127处理组与对照组之间的相对酶活性均无显著差异。综上所述，本研究的结果表明，P123和F127能够抑制肠道P-gp活性，但对肠道细胞色素P450 3A活性的影响很小或没有影响，这表明P123和F127可能作为药物成分，通过抑制P-gp外排泵来提高共给P-gp底物的口服生物利用度。
The aim of the present study was to evaluate the effect of pluronic P123 (P123) and pluronic F127 (F127) on intestinal P-glycoprotein (P-gp) and cytochrome P450 3A using the specific substrates rhodamine-123 (R-123) and midazolam, respectively. Caco-2 cells and everted gut sacs were used as models of intestinal mucosa to assess intestinal absorption of R-123, while rat intestinal microsomes were utilized to examine the effect of P123 and F127 on in vitro midazolam metabolism. P123 and F127 were observed to increase the intracellular accumulation of R-123 in Caco-2 cells in a dose-dependent manner. P123 significantly lowered the efflux ratio of R-123 at two concentrations in Caco-2 monolayers, whereas F127 lowered the efflux ratio only at 1%. Moreover, both pluronics markedly enhanced mucosal to serosal absorption of R-123 in excised ileum of rats. However, no significant difference in relative enzyme activity were observed between P123- or F127-treated and control groups, regardless of the concentrations of P123 and F127 studied. Collectively, these results obtained from the present study demonstrated that P123 and F127 were capable of inhibiting the intestinal P-gp activity, but had little or no effect on intestinal cytochrome P450 3A activity, indicating that P123 and F127 can potentially be used as pharmaceutical ingredients to improve the oral bioavailability of coadministered P-gp substrates via P-gp efflux pump inhibition.