Intestinal membrane permeability

JH Kou, D Fleisher, GL Amidon. Calculation of the aqueous diffusion layer resistance for absorption in a tube Application to intestinal membrane permeability determination. Pharm Res 8 298-305, 1991. 

GL Amidon, PJ Sinko, D Fleisher. Estimating human oral fraction dose absorbed A correlation using rat intestinal membrane permeability for passive and carrier-mediated compounds. Pharm Res 5 651-654, 1988. 

Amidon GL, Sinko PJ and Fleisher D (1988) Estimating Human Oral Fraction Dose Absorbed—A Correlation Using Rat Intestinal-Membrane Permeability for Passive and Carrier-Mediated Compounds. Pharm Res 5 pp 651-654. 

The presence of folds and villi structures on the surface area is not taken into account for the in vivo effective intestinal membrane permeability (Pefr when extrapolated from a perfusion experiment, a smooth tube is usually assumed). In humans, the fold expansion (FE) of the surface area is about threefold, and villi expansion (VE) is about 10-fold [7]. In the case of high epithelial membrane permeability (Pep) absorption occurs at the top of the villi before diffusing down the villi channels, whereas low Pep compound may diffuse down the villi channels to the crypts (Figure 6.1). Therefore, accessibility (Acc) to the surface depends on Pep and diffusion coefficient [7, 8]. The effective membrane permeability can be expressed as ... 

Figure 6.2 Relationship between the epithelial membrane permeability and the effective intestinal membrane permeability in humans. Based on [6] an recalculated including fold expansion and UWL effect.

The rapid evaluation of the intestinal membrane permeability of drugs represents a continuing challenge. Human intubation studies have been used to measure jejeunal effective permeability of a number of drugs, and these measurements have been compared with the extent of drug absorption. It can be seen from Figure 4.6 that the expected fraction absorbed exceeds 95% for drugs with a jejeunal permeability of more than 2-4 x 10 cm/sec (29). 

Equation 18.4, then, it is apparent that the fliK of drug across the intestine is directly proportional to its aqueous solubility. For drugs that have high intestinal membrane permeability aqueous solubility may be the limiting factor to adequate drug absorption. Generally, only the un-ionized species is absorbed thus, for ionizable compounds, the concentration of the un-ionized form should be considered in Equation 18.4. 

Koga, K., Kusawake, Y., Ito, Y., Sugioka, N., Shibata, N., Takada, K., 2006. Enhancing mechanism of Labrasol on intestinal membrane permeability of the hydrophilic drug gentamicin sulfate. Eur. J. Pharm. Biopharm. 64, 82—91. 

Varghese Gupta, S., Gupta, D., Sun, J., Dahan, A., Tsume, Y., Hillinger, J., Lee, K.-D., and Amidon, GX. (2011) Enhancing the intestinal membrane permeability of zanamivir a carrier mediated prodrug approach. Molecular Pharmaceutics, 8, 2358-2367. 

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