PRINCIPLES OF TOXICOLOGY

2.2 TRANSFER ACROSS MEMBRANE BARRIERS
Every compound that reaches the systemic circulation and has not been intravenously injected has had
to cross membrane barriers. Therefore, the first topic to be considered is the membrane itself and what
enables a toxicant to cross it.
All membranes are similar in structure. They consist of a phospholipid bilayer, toward the interior
of which are positioned the long hydrocarbon or fatty acid tails of the phospholipids, and toward the
outside of which are the more polar and hydrophilic portions of the phospholipid molecules. The fatty
acid tails align themselves in the interior of the membrane in a formation that is relatively fluid at body
temperatures. The polar portions of the phospholipid molecules maintain a relatively rigid outer
structure. Proteins embedded throughout the lipid bilayer have specific functions that will be considered
later.
Molecules can traverse membranes by three principal mechanisms:
• Passive diffusion
• Facilitated diffusion
• Active transport
Passive Diffusion
2.2 TRANSFER ACROSS MEMBRANE BARRIERS 37
Passive transfer does not involve the participation of any membrane proteins. Two factors determine
the rate at which passive diffusion takes place across a membrane: (1) the difference between the
concentrations of the chemical on the two sides of the membrane and (2) the ease with which a molecule
of the chemical can move through the lipophilic interior of the membrane. Three major factors affect
ease of passage: lipid solubility, or lipophilicity; molecular size; and degree of ionization.
The Partition Coefficient The lipid solubility of a compound is frequently expressed by its partition
coefficient. The partition coefficient is defined as the concentration of the chemical in an organic phase
divided by its concentration in water at equilibrium between the two phases. The organic phase is often
chloroform, hexane or heptane, or octanol. The partition coefficient is determined by shaking the
chemical with water and the organic solvent, and measuring the concentration of the chemical in each
phase when equilibrium has been reached.
Although the partition coefficient does not have much meaning as an absolute value, it is very useful
as an expression of the relative lipophilicities of a series of compounds. It is the rank order that is
meaningful in most cases. For example, it has been shown that the partition coefficients of the
nonionized forms of several series of representative drugs can be correlated with their rates of transfer
across a number of biological membrane systems—from intestinal lumen into blood, from plasma into
brain and into cerebrospinal fluid, and from lung into blood. In general, as lipophilicity increases, the
partition coefficient increases, and so does ease of movement through the membrane (Table 2.1).
Molecular Size The second important feature of a molecule determining ease of movement across
a membrane is molecular size. As the cylindrical radius of the molecule increases, with lipophilicity
remaining approximately constant, rate of movement across the membrane decreases. This is because
the transfer of larger molecules is slowed by frictional resistance and, depending on the structure of
the molecule, may also be slowed by steric hindrance. Figure 2.2 illustrates the dependence of the
permeability coefficient/partition coefficient ratio on molecular size in a series of lipophilic amides.
The ratio would be constant if molecular size were not important. In this set of amides, both molecular
size and steric hindrance (the branched-chain forms) are factors in slowing the diffusion of the larger
molecules. Very small molecules, in contrast, may move across the membrane more rapidly than would
be predicted on the basis of their partition coefficients alone. Small molecules are likely to be more