Advertisement

Rapid Permeability Screening in Drug Discovery to Predict Human Intestinal Absorption

  • G. S. J. Mannens
  • H. Bohets
  • P. Verboven
  • K. Steemans
  • K. Lavrijsen
  • W. Meuldermans
Part of the Ernst Schering Research Foundation Workshop book series (SCHERING FOUND, volume 37)

Abstract

After oral administration of a drug, several hurdles have to be passed before the drug becomes systemically available. First of all, the drug has to be liberated from the pharmaceutical formulation. Within the gastrointestinal (GI) tract, the drug has to be resistant to enzymes and different pH environments. The dissolved compound has to be absorbed through the intestinal cell layer, which means it has to traverse many barriers formed by cell membranes. These cell membranes are composed of phospholipid bilayers, which are oily barriers that hinder the passage of charged or hydrophilic molecules. After absorption from the intestinal tract, the compound can reach the systemic blood stream via the portal vein through the liver. First pass metabolism in the intestine and in the liver and biliary excretion can limit the systemic availability.

Keywords

Drug Discovery MDCK Cell Marker Compound Artificial Membrane Unstirred Water Layer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Avdeef A (2001) High-throughput solubility measurements. In: Testa B, van de Waterbeemd H, Folkers G, Guy R (eds) Pharmacokinetic optimization in drug research. Verlag Helvetica Chimica Acta, Zürich, pp 305–326CrossRefGoogle Scholar
  2. Delie F, Rubas W (1997) A human colonic cell line sharing similarities with enterocytes as a model to examine oral absorption: advantages and limitations of the Caco-2 model. Critic Rev Ther Drug Carrier Syst 14: 221–286Google Scholar
  3. Hidalgo J, Hillgren KM, Grass GM, Borchadt RT (1991) Characterization of the unstirred water layer in Caco-2 cell monolayer using a novel diffusion apparatus. Pharm Res 8: 222–227PubMedCrossRefGoogle Scholar
  4. Irvine JD, Takahashi L, Lockhart K, Cheong J, Tolan JW, Selick HE, Grove JR (1999) MDCK (Madin-Darby canine kidney) cells: a tool for membrane permeability screening. J Pharm Sci 88: 28–33PubMedCrossRefGoogle Scholar
  5. Kansy M, Senner F, Gubernator K (1998) Physicochemical high throughput screening: Parallel Artificial Membrane Permeation Assay in the description of passive absorption processes. J Med Chem 41: 1007–1010Google Scholar
  6. Karls son J, Artursson P (1991) A method for the determination of cellular permeability coefficients and aqueous boundary layer thickness in monolayers of intestinal epithelial (Caco-2) cells grown in permeable filter chambers. Int J Pharm 71: 55–64CrossRefGoogle Scholar
  7. Norris DA, Leesman GD, Sinko PJ, Grass GM (2000) Development of predictive pharmacokinetic simulation models for drug discovery. J Controlled Release 65: 55–62CrossRefGoogle Scholar
  8. Pade V, Stavchansky (1998) Link between drug absorption solubility and permeability measurements in Caco-2 cells. J Pharm Sci 87: 1604–1607Google Scholar
  9. Palm K, Luthman K, Ros J, Grasjo J, Artursson P (1999) Effect of molecular charge on intestinal epithelial drug transport: pH-dependent transport of cationic drugs. J Pharmacol Exp Ther 291: 435–443PubMedGoogle Scholar
  10. Takano M, Hasegawa R, Fukuda T, Yumoto R, Nagai J, Murakami T (1998) Interaction with P-glycoprotein and transport of erythromycin, midazolam and ketoconazole in Caco-2 cells. Eur J Pharmacol 358: 289–294PubMedCrossRefGoogle Scholar
  11. Wohnsland F, Faller B (2001) High-throughput permeability pH profile and high-throughput alkane/water log P with artificial membranes. J Med Chem 44: 923–930PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2002

Authors and Affiliations

  • G. S. J. Mannens
  • H. Bohets
  • P. Verboven
  • K. Steemans
  • K. Lavrijsen
  • W. Meuldermans

There are no affiliations available

Personalised recommendations