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The most convenient route of drug administration is oral. Along with the presence of proteolytic enzymes in the gastrointestinal tract, the intestinal mucosa represents the main barrier to the absorption of orally administered drugs into the systemic circulation. To overcome this biological barrier, drugs may cross the intestinal wall via transcellular or paracellular route. The transcellular pathway involves the passage of drugs through the cells, while the paracellular pathway refers to the passage of drugs between the adjacent cells, which is mostly restricted by tight junction proteins. The preferred pathway for absorption or transport of a specific drug depends on its physicochemical properties as well as the biological membrane features. Generally, lipophilic drugs pass through biological membrane by transcellular pathway, while hydrophilic drugs tend to path through the membrane paracellularly. Since absorption potential has become an important criterion in the discovery process, there is a need for reliable screening methods to assess compound permeability. Intestinal absorption screening assays should be highly predictive, fast, reliable, cost-effective, and require a small amount of compound.

Drug discovery scientists use many techniques to evaluate the intestinal permeability of drug candidates during the drug selection process. The most common preclinical methods currently used throughout the industry are: in vitro methods, for example, Ussing chamber or membrane vesicles based on animal tissue; cell-based assay systems such as Caco-2 cells and Mardin-Darby canine kidney (MDCK); artificial lipid-based systems such as parallel artificial membrane permeability assay (PAMPA) or immobilized artificial membranes (IAM); in vivo methods (animal pharmacokinetic studies); in situ methods (single-pass perfusion); and in silico (computer-aided drug design) methods. One, or a combination of these models, is commonly used in permeability assessment in drug discovery. A tiered approach is often used, which involves a high-throughput (but less predictive) model for primary screening, and then a low-throughput (but more predictive) model for secondary screening and mechanism study. The cell culture models strike the right balance between predictability and throughput, and are therefore the method of choice for permeability assessment across the pharmaceutical industry.

Table 1. Comparison of models for intestinal absorption of therapeutic compounds.

 CharacteristicsProsCons
In Silico
  • Computational model analysis based on the physicochemical properties of compounds
  • Quantitative structure-activity relationship (QSAR) model
  • Artificial neural networks
  • Quick and inexpensive method for assessing intestinal permeability
  • Not as reliable as real experimental data
In Vitro
  • Cultured cell monolayer: widely used in absorption studies
  • Less labor
  • Less cost-intensive
  • Benefits in terms of ethical considerations
  • Failure to consider the effect of physiological factors
  • Interlaboratory variation interferes with the extrapolation of in vitro transport data
In Situ
  • Perfusion of drug through isolated intestinal segment
  • Intact blood and nerve supply
  • Appears to correlate best with the human data
  • Massive animal consumption
  • High amounts of test compounds
  • Not sensitive enough to measure compounds with low or moderate permeability
Ex Vivo
  • Excised animal tissues mounted on Ussing chambers
  • Drug transport can be investigated
  • Amount of drug needed is relatively small
  • Time consuming
  • Difficult to perform epithelial tissue dissection
In Vivo
  • Commonly used animals include rats, monkeys, dogs and pigs, of which rats are the most frequently used
  • Integrate all dynamic components that may affect drug dissolution
  • Massive animal consumption
  • Time-consuming
  • Labor-intensive nature
  • Impossible to separate the variables involved in the process of absorption

References

  1. Antunes F. et al.; Models to predict intestinal absorption of therapeutic peptides and proteins. Curr Drug Metab. 2013, 14(1): 4-20.
  2. Alqahtani, S. et al.; Experimental models for predicting drug absorption and metabolism. Expert Opinion on Drug Metabolism & Toxicology, 2013, 9(10): 1241-1254.
  3. Billat P. A. et al.; Models for drug absorption from the small intestine: where are we and where are we going? Drug Discov Today, 2017, 22(5): 761-775.

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