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Comparison of Human Duodenum and Caco-2 Gene Expression Profiles for 12,000 Gene Sequences Tags and Correlation with Permeability of 26 Drugs

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Abstract

Purpose. To compare gene expression profiles and drug permeability differences in Caco-2 cell culture and human duodenum.

Methods. Gene expression profiles in Caco-2 cells and human duodenum were determined by GeneChip® analysis. In vivo drug permeability measurements were obtained through single-pass intestinal perfusion in human subjects, and correlated with in vitro Caco-2 transport permeability.

Results. GeneChip® analysis determined that 37, 47, and 44 percent of the 12,559 gene sequences were expressed in 4-day and16-day Caco-2 cells and human duodenum, respectively. Comparing human duodenum with Caco-2 cells, more than 1000 sequences were determined to have at least a 5-fold difference in expression. There were 26, 38, and 44 percent of the 443 transporters, channels, and metabolizing enzymes detected in 4-day, 16-day Caco-2 cells, and human duodenum, respectively. More than 70 transporters and metabolizing enzymes exhibited at least a 3-fold difference. The overall coefficient of variability of the 10 human duodenal samples for all expressed sequences was 31% (range 3% to 294%) while that of the expressed transporters and metabolizing enzymes was 33% (range 3% to 87%). The in vivo / in vitro drug permeability measurements correlated well for passively absorbed drugs (R2 = 85%). The permeability correlation for carrier-mediated drugs showed 3- 35-fold higher in human above the correlation of passively absorbed drugs. The 2- 595-fold differences in gene expression levels between the Caco-2 cells and human duodenum correlated with the observed 3- 35-fold difference in permeability correlation between carrier-mediated drugs and passively absorbed drugs.

Conclusions. Significant differences in gene expression levels in Caco-2 cells and human duodenum were observed. The observed differences of gene expression levels were consistent with observed differences in carrier mediated drug permeabilities. Gene expression profiling is a valuable new tool for investigating in vitro and in vivo permeability correlation.

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Author notes

  1. Duxin Sun

    Present address: Department of Biopharmaceutics and Stability, Pharmaceutical Research Institute, Bristol-Myers Squibb Company, New Brunswick, New Jersey, 08903

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, Michigan, 48109

    Duxin Sun, Lynda S. Welage, Christopher P. Landowski, David Foster, David Fleisher, Kyung-Dall Lee & Gordon L. Amidon

  2. Department of Pharmacy, Group of Biopharmaceutics, Uppsala University, Box 580, S-751 23, Uppsala, Sweden

    Hans Lennernas

  3. Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, 48109

    Jeffery L. Barnett

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Sun, D., Lennernas, H., Welage, L.S. et al. Comparison of Human Duodenum and Caco-2 Gene Expression Profiles for 12,000 Gene Sequences Tags and Correlation with Permeability of 26 Drugs. Pharm Res 19, 1400–1416 (2002). https://doi.org/10.1023/A:1020483911355

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