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Abstract

GeneChip analysis determined that 37, 47, and 44 percent of the 12,559 gene sequences were expressed in 4-day andl6-day Caco-2 cells and human duodenum, respectively. Comparing human duodenum with Caco-2 cells, more than 1,000 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.

Transepithelial Transport of PAMAM Dendrimers Across Isolated Human Intestinal Tissue

“…The difference between Caco-2 and isolated tissue models may be caused by the lack of mucous, supportive cells and morphology which are present in isolated tissue models. 17,35,36 The permeability of mannitol was significantly increased in colonic epithelium treated with G3.5-COOH and G4-NH 2 dendrimers at 10mM concentrations. 10mM concentrations did not however significantly enhance the mannitol permeability in jejunal segments.…”

Translating Human Effective Jejunal Intestinal Permeability to Surface-Dependent Intrinsic Permeability: a Pragmatic Method for a More Mechanistic Prediction of Regional Oral Drug Absorption

“…Those jejunal P eff values are currently limited to only 30 drugs (3)(4)(5). Therefore, its application to drugs not listed in the current datasets depends on the availability of in vivo, in vitro or in silico methods for the prediction of jejunal P eff (59,60,(77)(78)(79)(80)(81)(82). Due to the use of P eff for this study, regional differences in the transport mechanisms of the drugs involved herein were not explicitly considered (e.g.…”

Simulating Intestinal Transporter and Enzyme Activity in a Physiologically Based Pharmacokinetic Model for Tenofovir Disoproxil Fumarate

“…The authors hypothesized that this was the result of active transport saturation (specifically, saturation of ABCB1) when higher TDF concentrations were added to the receiver compartment. To inform the current model of this scenario, this relationship between TDF concentrations and P app was continuously redetermined in each intestinal segment using the following polynomial equation, derived from a previous study (7) Using previously established equations, P app was used to generate the rate of drug absorption in the model (18,19). Intestinal absorption of TFV, the breakdown product of TDF occurring via luminal lipase, was included.…”