Comparison of human duodenum and Caco-2 gene expression profiles for 12,000 gene sequences tags and correlation with permeability of 26 drugs

Duxin Sun, Hans Lennernas, Lynda S. Welage, Jeffery L. Barnett, Christopher P. Landowski, David Foster, David Fleisher, Kyung Dall Lee, Gordon L. Amidon

Research output: Contribution to journalArticleScientificpeer-review

293 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1400-1416
Number of pages17
JournalPharmaceutical Research
Volume19
Issue number10
DOIs
Publication statusPublished - 1 Oct 2002
MoE publication typeA1 Journal article-refereed

Keywords

  • Gene expression
  • GeneChip®
  • In vivo/in vitro correlation
  • Permeability
  • Transporter

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