Chemical Barriers To Drug Delivery

The chemical structure of a drug determines its solubility and permeability profiles. In turn, the concentration at the intestinal lumen and the permeation of the drug across the intestinal mucosa are responsible for the rate and extent of absorption.39 Unfavorable physicochemical properties have been a limiting factor in the oral absorption of peptides and peptidomimetics.40 The structural factors involved in the permeation of peptides will be described here.

2.4.1. Hydrogen-Bonding Potential

Hydrogen-bonding potential has been shown to be an important factor in the permeation of peptides. Studies in vivo and in various cell culture models of the blood-brain barrier and intestinal mucosa indicate that desolvation or hydrogen-bonding potential regulates the permeation of peptides.39,41-43 The energy needed to de-solvate the polar amide bonds in the peptide to allow it to enter and traverse the cell membrane is the principle behind the concept of hydrogen-bonding potential. For small organic molecules, the octanol-water partition coefficient is the best predictor of cell membrane permeation with a sigmoidal relationship.42 However, this is not the case with peptides; the desolvation energy or hydrogen-bonding potential is a better predictor for membrane permeation of peptides. Burton et al. have reported partition coefficients of model peptides in n-octanol/Hanks' balanced salt solution (HBSS), isooctane/HBSS, and heptane/ethylene glycol systems.41 Two experimental methods were developed to measure the desolvation energy or the hydrogen-bonding potential of peptides. In the first method, the hydrogen-bonding potential is calculated from the difference between the partition coefficients of octanol/water and isooctane/water. The second method involves measuring the partition coefficient of peptide in heptane/ethylene glycol; this method correlates well with the hydrogen-bonding potential and provides a simpler and more direct measurement.41

2.4.2. Other Properties

Physicochemical properties of the peptide are also important determinants in the passage of drugs via the paracellular path. Size, charge, and hydrophilicity are the factors influencing paracellular permeation.40 A change in the hydrophilicity of a peptide may alter its route of permeation; as the hydrophilicity of a peptide decreases, its lipophilicity increases, causing a shift in permeation of the peptide from the paracellular to the transcellular route. Molecules with radii larger than 11 A are unable to penetrate the tight junctions.44 Studies of Caco-2 cells confirm that drug permeation via the paracellular path is size-dependent, and this highlights the sieving abilities of the intercellular junctions.40

Although the paracellular path is negatively charged, the effect of charge on paracellular permeation is not well understood. One study suggests that a positive net charge on a peptide produces the best paracellular permeation, but another study suggests that a — 1 or —2 charge is most effective in paracellular transport.40 It has also been suggested that the effect of charge is negligible as the molecular size of the peptide increases.40

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