Why is it challenging to predict intestinal drug absorption and oral bioavailability in human using rat model
Why is it challenging to predict intestinal drug absorption and oral bioavailability in human using rat model
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DOI：
10.1007/s11095-006-9041-2
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发表时间：
2006-08-01
影响因子：
3.7
通讯作者：
Sun, Duxin
中科院分区：
文献类型：
--
作者：
Cao, Xianhua;Gibbs, Seth T.;Sun, Duxin
目的.研究不同吸收途径药物在人体和大鼠肠道吸收的相关性，探讨人体和大鼠肠道吸收相似性和口服生物利用度差异的分子机制。采用在体肠灌流法测定了14种药物及3种不同吸收机制的类药物化合物在大鼠和人空肠中的肠渗透性。共选择了48种药物进行口服生物利用度比较。利用基因芯片技术分析了大鼠和人肠道（十二指肠和结肠）转运蛋白和代谢酶的表达谱。大鼠和人之间的口服药物生物利用度没有相关性（r（2）= 0.29），而人和大鼠小肠之间的载体介导的吸收和被动扩散机制的药物肠道渗透性观察到相关性（r（2）= 0.8）。人和大鼠十二指肠中转运蛋白的表达水平也存在中等程度的相关性（r（2）> 0.56），这为两个物种之间药物吸收的相似性和相关性提供了分子机制。与此相反，大鼠和人类肠道中的代谢酶的表达没有发现相关性，这表明药物代谢和口服生物利用度在两个物种中的差异。详细的分析表明，许多转运蛋白（如PepT 1，SGLT-1，GLUT 5，MRP 2，NT 2和高亲和力谷氨酸转运蛋白）在人和大鼠中具有相似的表达水平，具有区域依赖性表达模式，在小肠中高表达，在结肠中低表达。然而，在人和大鼠的十二指肠和结肠中也观察到其他几种转运蛋白（如MDR 1，MRP 3，GLUT 1和GLUT 3）的差异。此外，代谢酶（CYP 3A 4/CYP 3A 9和UDPG）在人和大鼠肠道中的表达差异为12 ~ 193倍，且具有明显的区域依赖性表达模式。数据表明，大鼠和人显示出相似的药物肠道吸收谱和小肠中相似的转运蛋白表达模式，而这两个物种在肠道中表现出不同的代谢酶表达水平和模式。因此，大鼠模型可用于预测口服药物在人体小肠中的吸收，但不能预测药物代谢或人体口服生物利用度。
Purpose. To study the correlation of intestinal absorption for drugs with various absorption routes between human and rat, and to explore the underlying molecular mechanisms for the similarity in drug intestinal absorption and the differences in oral bioavailability between human and rat.Materials and Methods. The intestinal permeabilities of 14 drugs and three drug-like compounds with different absorption mechanisms in rat and human jejunum were determined by in situ intestinal perfusion. A total of 48 drugs were selected for oral bioavailability comparison. Expression profiles of transporters and metabolizing enzymes in both rat and human intestines (duodenum and colon) were measured using GeneChip analysis.Results. No correlation (r(2) = 0.29) was found in oral drug bioavailability between rat and human, while a correlation (r(2) = 0.8) was observed for drug intestinal permeability with both carrier-mediated absorption and passive diffusion mechanisms between human and rat small intestine. Moderate correlation (with r(2) > 0.56) was also found for the expression levels of transporters in the duodenum of human and rat, which provides the molecular mechanisms for the similarity and correlation of drug absorption between two species. In contrast, no correlation was found for the expressions of metabolizing enzymes between rat and human intestine, which indicates the difference in drug metabolism and oral bioavailability in two species. Detailed analysis indicates that many transporters (such as PepT1, SGLT-1, GLUT5, MRP2, NT2, and high affinity glutamate transporter) share similar expression levels in both human and rat with regional dependent expression patterns, which have high expression in the small intestine and low expression in the colon. However, discrepancy was also observed for several other transporters (such as MDR1, MRP3, GLUT1, and GLUT3) in both the duodenum and colon of human and rat. In addition, the expressions of metabolizing enzymes (CYP3A4/CYP3A9 and UDPG) showed 12 to 193-fold difference between human and rat intestine with distinct regional dependent expression patterns.Conclusions. The data indicate that rat and human show similar drug intestinal absorption profiles and similar transporter expression patterns in the small intestine, while the two species exhibit distinct expression levels and patterns for metabolizing enzymes in the intestine. Therefore, a rat model can be used to predict oral drug absorption in the small intestine of human, but not to predict drug metabolism or oral bioavailability in human.