Why is it challenging to predict intestinal drug absorption and oral bioavailability in human using rat model.
OBJECTIVE
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.


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.
Cao
Xianhua
X
Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, USA.
Gibbs
Seth T
ST
Fang
Lanyan
L
Miller
Heather A
HA
Landowski
Christopher P
CP
Shin
Ho-Chul
HC
Lennernas
Hans
H
Zhong
Yanqiang
Y
Amidon
Gordon L
GL
Yu
Lawrence X
LX
Sun
Duxin
D
D000818:Animals; D001682:Biological Availability; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003106:Colon / Q000378:metabolism; D003627:Data Interpretation, Statistical; D004386:Duodenum / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D010477:Perfusion; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011237:Predictive Value of Tests; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D018075:RNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
D002352:Carrier Proteins; D004364:Pharmaceutical Preparations; D018075:RNA, Complementary; D012313:RNA