Permeability dominates in vivo intestinal absorption of P-gp substrate with high solubility and high permeability
Permeability dominates in vivo intestinal absorption of P-gp substrate with high solubility and high permeability
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DOI：
10.1021/mp0499104
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发表时间：
2005-07-01
影响因子：
4.9
通讯作者：
Sun, Duxin
中科院分区：
文献类型：
--
作者：
Cao, Xianhua;Yu, Lawrence X.;Sun, Duxin
本研究有三个目的：（1）研究具有高溶解度和高渗透性的P-gp底物的体内区域依赖性肠吸收，（2）研究肠不同区域的基因表达差异，（3）研究P-gp或任何其他转运蛋白对P-gp底物吸收的贡献。采用大鼠在体肠灌流法测定维拉帕米和普萘洛尔的在体渗透性。使用Affyssin基因芯片测量基因表达谱。采用非参数bootstrap法和方差分析对3500个基因的表达与药物体内渗透性进行相关性分析。维拉帕米和普萘洛尔的渗透性没有表现出区域依赖性，即使在肠道的各个区域观察到基因表达的显着差异。维拉帕米的渗透性显着相关普萘洛尔在空肠和回肠的渗透性，但没有相关性与其他亲水性化合物（伐昔洛韦，阿昔洛韦，苯丙氨酸）的渗透性。四个不同的区域（十二指肠、空肠、回肠和结肠）显示出不同的基因表达模式，其中超过70-499个基因显示出至少5倍的表达差异。有趣的是，P-gp表达从十二指肠到结肠逐渐增加6倍。尽管在肠道的各个区域有不同的基因表达模式，维拉帕米的渗透性与肠道中3500个表达基因中的任何基因表达都不相关。2-6倍的P-gp表达差异似乎与维拉帕米在体内不同肠区的渗透性无关。这些数据表明，P-gp在维拉帕米的体内肠吸收过程中起着最小的作用，具有高水溶性和高膜渗透性。维拉帕米在体内的肠吸收主要由其高渗透性决定。然而，值得注意的是，本文的研究结果并没有削弱P-gp在口服药物生物利用度、肝脏药物处置、血脑屏障药物外排和药物相互作用中的重要性。
Three purposes are presented in this study: (1) to study the in vivo regional dependent intestinal absorption of a P-gp substrate with high solubility and high permeability, (2) to study the gene expression difference in the various regions of the intestine, and (3) to study the contributions of P-gp or any other transporters for the absorption of a P-gp substrate. The in vivo permeability of verapamil and propranolol were determined by single-pass in situ intestinal perfusion in rat. The gene expression profiles were measured using Affymetrix GeneChip. Correlation analysis between drug in vivo permeability and expression of 3500 genes was performed with nonparametric bootstrap and ANOVA analysis. The permeability of verapamil and propranolol did not demonstrate regional dependency even though significant differences in gene expression were observed in various regions of the intestine. Verapamil permeability significantly correlates with propranolol permeability in both jejunum and ileum, but did not correlate with the permeability of other hydrophilic compounds (valacyclovir, acyclovir, and phenylalanine). Four different regions (duodenum, jejunum, ileum, and colon) showed distinct gene expression patterns with more than 70-499 genes showing at least 5-fold expression differences. Interestingly, P-gp expression is gradually increased by 6-fold from the duodenum to colon. Despite the distinct gene expression patterns in the various regions of the intestine, verapamil permeability did not correlate with any gene expression from 3500 expressed genes in the intestine. A 2-6-fold P-gp expression difference did not seem to associate verapamil permeability in the various intestinal regions in vivo. These data suggest that P-gp plays a minimal role in the in vivo intestinal absorption process of verapamil with high water solubility and high membrane permeability. The intestinal absorption of verapamil in vivo is primarily dominated by its high permeability. However, it is important to note that the findings in this paper do not undermine the importance of P-gp in oral drug bioavailability, drug disposition from the liver, drug efflux from the blood-brain barrier, and drug-drug interaction.