Pharmaceutical Research

, Volume 23, Issue 8, pp 1675–1686

Why is it Challenging to Predict Intestinal Drug Absorption and Oral Bioavailability in Human Using Rat Model

  • Xianhua Cao
  • Seth T. Gibbs
  • Lanyan Fang
  • Heather A. Miller
  • Christopher P. Landowski
  • Ho-Chul Shin
  • Hans Lennernas
  • Yanqiang Zhong
  • Gordon L. Amidon
  • Lawrence X. Yu
  • Duxin Sun
Featured Article

DOI: 10.1007/s11095-006-9041-2

Cite this article as:
Cao, X., Gibbs, S.T., Fang, L. et al. Pharm Res (2006) 23: 1675. doi:10.1007/s11095-006-9041-2

Abstract

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 (r2 = 0.29) was found in oral drug bioavailability between rat and human, while a correlation (r2 = 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 r2 > 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.

Key words

drug transporter gene expression inter-species correlation intestinal permeability metabolizing enzyme oral bioavailability 

Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  • Xianhua Cao
    • 1
  • Seth T. Gibbs
    • 1
  • Lanyan Fang
    • 1
  • Heather A. Miller
    • 1
  • Christopher P. Landowski
    • 2
  • Ho-Chul Shin
    • 2
  • Hans Lennernas
    • 3
  • Yanqiang Zhong
    • 2
  • Gordon L. Amidon
    • 2
  • Lawrence X. Yu
    • 4
  • Duxin Sun
    • 1
  1. 1.Division of Pharmaceutics, College of PharmacyThe Ohio State UniversityColumbusUSA
  2. 2.Department of Pharmaceutical SciencesCollege of Pharmacy, University of MichiganAnn ArborUSA
  3. 3.Department of PharmacyGroup of Biopharmaceutics Uppsala UniversityUppsalaSweden
  4. 4.Office of Generic DrugsCenter for Drug Evaluation and Research, Food and Drug AdministrationRockvilleUSA

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