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Comparison of Caco-2 with Other Cell-based Models for Intestinal Permeability Studies
[email protected] Bioarray
Intestinal Drug Absorption
Cell-based Models for Intestinal Permeability Studies
Intestinal drug absorption is one of the factors that determine the success of an oral drug product along with its efficacy, pharmacokinetics, and toxicity. Therefore, models for predicting intestinal drug absorption are becoming more important in early drug development to accelerate identification of promising or troublesome compounds.
The use of cell cultures provides a method to predict drug permeability by utilizing cell monolayers in a two-chamber diffusion system to simulate the passage of drugs from the intestinal lumen into the blood. The cell model is simple and easy to use and avoids the usage of animal models for pharmacological and toxicological studies, so it is cost-effective and can produce reliable and reproducible results for understanding and evaluating the permeability characteristics of the potential lead drug candidates.
Caco-2
MDCK
HT29-MTX
2/4/A1
TC-7
LLC-PK1
IEC-18
T84
Many cell monolayer models have been developed to mimic
human intestinal epithelium and are gaining in popularity.
These models use immortalized cells that grow
rapidly into confluent monolayers and undergo
spontaneous differentiation. Therefore, these cell
monolayer models provide an ideal system for the study of intestinal drug absorption.
Cell-based Models for Intestinal Permeability Studies
Cell-based Models for Intestinal Permeability StudiesCaco-2 Cell Line
Characteristics
Polarized monolayers with tight junction, brush border and apical
microvilliExpression of some
relevant efflux transporters
Advantages
Well-developed and characterized
Good reproducibility, robustness and functional
property of human intestinal cells
Origin
Human colon adenocarcinoma
Limitations
Absence of mucous secreting goblet cells Expression of influx
transporters is variable Not suitable for
paracellular transport 21-days culture period
5
3-5 days culture period Ideal for transfections
Advantages
Under-expression of major efflux transporters Not for active and efflux studiesNot for mechanistic studies
Limitations
Polarized cells with low intrinsic expression of ABC transporters
Characteristics
Dog kidneyOrigin
Cell-based Models for Intestinal Permeability StudiesMDCK Cell Line
6
Advantages
Higher levels of CYP3A4 and 3A5Useful to evaluate metabolic effects during transportGreater homogeneity ensuring more consistent results with lower variability
Limitations
Similar to Caco-2
Origin
Caco-2 subclone
Characteristics
Low expression of P-gpStable expression of CYP3A4
TC7
Cell-based Models for Intestinal Permeability StudiesTC7 Cell Line
Human colon carcinoma
Origin
Multilayer of undifferentiated cellsLack tight junction & functional polarity
Characteristics
Contain mucus-producing goblet cells
Advantages
Not suitable for carrier-mediated transport
Unstable mucus layer
Limitations
Cell-based Models for Intestinal Permeability StudiesHT29-MTX Cell Line
Origin
Fetal rat intestine
Characteristics
Polarized monolayers with tight junction, brush border
membrane enzymes and transporter proteins
Advantages
Temperature-sensitive Ideal for paracellularly
absorbed compounds (leakier pores)
Good for medium to low throughput screening
Limitations
Lack enzyme systems, transporters fond in Caco-2
and small intestine Less pharmaceutical use
Cell-based Models for Intestinal Permeability Studies2/4/A1 Cell Line
Advantages
Better model for epithelial permeability study of hydrophilic molecules than Caco-2Provides a size-selective barrier for paracellularly transported compounds
Limitations
Not for cell mediated transport studies
Origin
Rat intestine
Characteristics
Poor cell differentiationLeakier paracellular pathway
Cell-based Models for Intestinal Permeability StudiesIEC-18 Cell Line
IEC-18
Limitations
Not adequate for drug studies and carrier mediated process
Characteristics
Not well differentiated cells
Advantages
Resemble colonic crypt cell phenotype
Origin
Human colon cancer
Cell-based Models for Intestinal Permeability StudiesT84 Cell Line
Cell-based Models for Intestinal Permeability StudiesLLC-PK1 Cell Line
Pig kidneyPolarized cells with low
intrinsic transporter expression
Characterization of passive transport
Ideal for transfections
Not for active and efflux studies
Not for mechanistic studies
Origin Characteristics Advantages Limitations
Conclusion
Although all of these cell models show good or moderate correlations with passively absorbed drug permeability in humans, correlations with active transport are variable and mainly low. However, even if in vivo correlation is slow, they are interesting models for determining drug transport mechanism, and extensive studies are needed to identify the relevant carriers and active transport mechanisms.
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