Cao Xianhua, Gibbs Seth T, Fang Lanyan, Miller Heather A, Landowski Christopher P, Shin Ho-Chul, Lennernas Hans, Zhong Yanqiang, Amidon Gordon L, Yu Lawrence X, Sun Duxin
Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, USA.
Pharm Res. 2006 Aug;23(8):1675-86. doi: 10.1007/s11095-006-9041-2.
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.
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.
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.
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.
研究人与大鼠不同吸收途径药物的肠道吸收相关性,探讨人与大鼠药物肠道吸收相似性及口服生物利用度差异的潜在分子机制。
采用原位肠灌注法测定14种药物及3种具有不同吸收机制的类药化合物在大鼠和人空肠中的肠道通透性。共选择48种药物进行口服生物利用度比较。采用基因芯片分析测定大鼠和人肠道(十二指肠和结肠)中转运体和代谢酶的表达谱。
大鼠与人的口服药物生物利用度无相关性(r² = 0.29),而人与大鼠小肠中载体介导吸收和被动扩散机制的药物肠道通透性具有相关性(r² = 0.8)。人与大鼠十二指肠中转运体的表达水平也存在中度相关性(r² > 0.56),这为两种物种药物吸收的相似性和相关性提供了分子机制。相比之下,大鼠与人肠道中代谢酶的表达无相关性,这表明两种物种在药物代谢和口服生物利用度方面存在差异。详细分析表明,许多转运体(如PepT1、SGLT - 1、GLUT5、MRP2、NT2和高亲和力谷氨酸转运体)在人和大鼠中具有相似的表达水平,并呈现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,其他几种转运体(如MDR1、MRP3、GLUT1和GLUT3)也存在差异。此外,代谢酶(CYP3A4/CYP3A9和UDPG)的表达在人和大鼠肠道之间相差12至193倍,且具有明显的区域依赖性表达模式。
数据表明,大鼠和人在小肠中表现出相似的药物肠道吸收谱和相似的转运体表达模式,而两种物种在肠道中代谢酶的表达水平和模式不同。因此,大鼠模型可用于预测人小肠中的口服药物吸收,但不能预测人药物代谢或口服生物利用度。