Abbreviation: Ko/w, oil/water partition coefficient.

measurement of differences in electrical potential (streaming potentials) across the membrane. The more permeable the compound, the smaller the osmotic pressure it exerts and the smaller the osmotic fluid flow it produces in the opposite direction; this results in a small potential difference. If the compound is impermeable, it produces a large osmotic pressure and osmotic fluid flow, resulting in a large potential difference. Experimentally, one exposes the mucosal membrane surface to a buffer solution containing a reference compound to which the membrane is completely impermeable (e.g., mannitol) and measures the resulting potential difference. This is followed by exposing the same membrane to a solution of a test compound and again measuring the resulting potential difference. The ratio of the potential difference of the test compound to that of the reference compound is referred to as the reflection coefficient (s). The s is a measure of the permeability of the test compound relative to a reference solute with the particular membrane being used. The less permeable the test compound, the closer the s approaches 1 (s = 1); the more permeable the test compound, the closer the s approaches 0 (s = 0).

By using this method, Wright and Diamond were able to reach a number of important conclusions concerning patterns of nonelectrolyte permeability. In general, membrane permeability of a solute increases with Ko/w, supporting previous findings mentioned earlier. The two classes of exceptions to this pattern are highly branched compounds, which penetrate the membrane more slowly than would be expected on the basis of their Ko/w, and smaller polar molecules, which penetrate the membrane more readily than would be expected on the basis of their Ko/w. The latter observation has been reported by other workers, and, as noted earlier, it has resulted in the development of the lipid-sieve membrane concept whereby one envisions aqueous pores in the membrane surface. The authors postulate that these small, polar, relatively lipid-insoluble compounds penetrate the membrane by following a route lined by the polar groupings of membrane constituents (i.e., localized polar regions). This concept is an attractive structural explanation of what have been referred to as pores. The accessibility of this route would be limited primarily by the molecular size of the compound as a result of steric hindrance. In fact, it is the first one or two members of a homologous series of compounds that are readily permeable, but beyond these members, it is primarily Ko/w that dictates permeability. Table 3 illustrates this effect for several members of various

Table 3 Influence of Chain Length on Membrane Permeability Within Several Homologous Series

Compound Reflection coefficient, s

Methyl urea 0.54

Ethyl urea 0.92

Propyl urea 0.93 -

Butyl urea 0.70 #

Malononitrile 0.09 "

Succinonitrile 0.30 -

Glutaronitrile 0.21 #

Methylformamide 0.28 "

Methylacetamide 0.51 -

Methylproprionamide 0.22 #

The reflection coefficient s is defined in the text. The direction of the arrows indicates an increase in permeability from the least permeable member of the series.

homologous series. Recall that the smaller the s, the more permeable the compound. In each instance, permeability decreases after the first member, reaches a minimum, and then increases again.

The other anomalous behavior was the smaller-than-expected permeability of highly branched compounds. This deviation has been explained on the basis that membrane lipids are subject to a more highly constrained orientation (probably a parallel configuration of hydrocarbon chains of fatty acids) than are those in a bulk lipid solvent. As a result, branched compounds must disrupt this local lipid structure of the membrane and will encounter greater steric hindrance than will a straight-chain molecule. This effect with branched compounds is not adequately reflected in simple aqueous lipid-partitioning studies (i.e., in the Ko/w value).

With the exception of rather small polar molecules, the majority of compounds, including drugs, appear to penetrate biological membranes via a lipid route. As a result the membrane permeability of most compounds is dependent on Ko/w. The physicochemical interpretation of this general relationship is based on the atomic and molecular forces to which the solute molecules are exposed in the aqueous and lipid phases. Thus, the ability of a compound to partition from an aqueous to a lipid phase of a membrane involves the balance between solute-water and solute-membrane intermolecular forces. If the attractive forces of the solute-water interaction are greater than those of the solute-membrane interaction, membrane permeability will be relatively poor and vice versa. In examining the permeability of a homologous series of compounds and, therefore, the influence of substitution or chain length on permeability, one must recognize the influence of the substituted group on the intermolecular forces in aqueous and membrane phases (e.g., dipole-dipole, dipole-induced dipole, or van der Waals forces). The membrane permeabilities of the nonelectrolytes studied appear to be largely determined by the number and strength of hydrogen bonds the solute can form with water. Thus, nonelectrolyte permeation is largely a question of physical organic chemistry in aqueous solution. Table 4 summarizes some of the interesting findings of Diamond and Wright with respect to the influence of substituent groups on membrane permeation. These data have been interpreted on the basis of the solutes' ability to form hydrogen bonds with water.

Table 4 Influence of Chemical Substitution on the Membrane Permeability of Several Series of Nonelectrolytes

Substituent group

Influence on membrane permeability



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