PRINCIPLES OF TOXICOLOGY - Biology East Borneo

2.2 TRANSFER ACROSS MEMBRANE BARRIERS 372.2 TRANSFER ACROSS MEMBRANE BARRIERSEvery compound that reaches the systemic circulation and has not been intravenously injected has hadto cross membrane barriers. Therefore, the first topic to be considered is the membrane itself and whatenables a toxicant to cross it.All membranes are similar in structure. They consist of a phospholipid bilayer, toward the interiorof which are positioned the long hydrocarbon or fatty acid tails of the phospholipids, and toward theoutside of which are the more polar and hydrophilic portions of the phospholipid molecules. The fattyacid tails align themselves in the interior of the membrane in a formation that is relatively fluid at bodytemperatures. The polar portions of the phospholipid molecules maintain a relatively rigid outerstructure. Proteins embedded throughout the lipid bilayer have specific functions that will be consideredlater.Molecules can traverse membranes by three principal mechanisms:• Passive diffusion• Facilitated diffusion• Active transportPassive DiffusionPassive transfer does not involve the participation of any membrane proteins. Two factors determinethe rate at which passive diffusion takes place across a membrane: (1) the difference between theconcentrations of the chemical on the two sides of the membrane and (2) the ease with which a moleculeof the chemical can move through the lipophilic interior of the membrane. Three major factors affectease 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 partitioncoefficient. The partition coefficient is defined as the concentration of the chemical in an organic phasedivided by its concentration in water at equilibrium between the two phases. The organic phase is oftenchloroform, hexane or heptane, or octanol. The partition coefficient is determined by shaking thechemical with water and the organic solvent, and measuring the concentration of the chemical in eachphase when equilibrium has been reached.Although the partition coefficient does not have much meaning as an absolute value, it is very usefulas an expression of the relative lipophilicities of a series of compounds. It is the rank order that ismeaningful in most cases. For example, it has been shown that the partition coefficients of thenonionized forms of several series of representative drugs can be correlated with their rates of transferacross a number of biological membrane systems—from intestinal lumen into blood, from plasma intobrain and into cerebrospinal fluid, and from lung into blood. In general, as lipophilicity increases, thepartition 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 acrossa membrane is molecular size. As the cylindrical radius of the molecule increases, with lipophilicityremaining approximately constant, rate of movement across the membrane decreases. This is becausethe transfer of larger molecules is slowed by frictional resistance and, depending on the structure ofthe molecule, may also be slowed by steric hindrance. Figure 2.2 illustrates the dependence of thepermeability 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 molecularsize and steric hindrance (the branched-chain forms) are factors in slowing the diffusion of the largermolecules. Very small molecules, in contrast, may move across the membrane more rapidly than wouldbe predicted on the basis of their partition coefficients alone. Small molecules are likely to be more