PROPERTIES OF BIOLOGICAL MEMBRANES THAT INFLUENCE DRUG PASSAGE
Although some substances are translocated by special-ized transport mechanisms and small polar compounds may filter through membrane pores, most foreign com-pounds penetrate cells by diffusing through lipid mem-branes. A model of membrane structure, shown in Figure 3.2, envisions the membrane as a mosaic struc-ture composed of a discontinuous bimolecular lipid layer with fluidlike properties. A smaller component consists of glycoproteins or lipoproteins that are em-bedded in the lipid matrix and have ionic and polar groups protruding from one or both sides of the mem-brane. This membrane is thought to be capable of un-dergoing rapid local shifts, whereby the relative geome- try of specific adjacent proteins may change to form channels, or pores. The pores permit the membrane to be less restrictive to the passage of low-molecular-weight hydrophilic substances into cells. In addition to its role as a barrier to solutes, the cell membrane has an important function in providing a structural matrix for a variety of enzymes and drug receptors. The model de-picted is not thought to apply to capillaries.
The ability of a drug to diffuse across membranes is fre-quently expressed in terms of its lipid–water partition co-efficient rather than its lipid solubility per se. This coeffi-cient is defined as the ratio of the concentration of the drug in two immiscible phases: a nonpolar liquid or or-ganic solvent (frequently octanol), representing the mem-brane; and an aqueous buffer, usually at pH 7.4, repre-senting the plasma. The partition coefficient is a measure of the relative affinity of a drug for the lipid and aqueous phases. Increasing the polarity of a drug, either by in-creasing its degree of ionization or by adding a carboxyl, hydroxyl, or amino group to the molecule, decreases the lipid–water partition coefficient. Alternatively, reducing drug polarity through suppression of ionization or adding lipophilic (e.g., phenyl or t-butyl) groups results in an in-crease in the lipid–water partition coefficient
Drugs, like most organic electrolytes, generally do not completely dissociate (i.e., form ions) in aqueous so-lution. Only a certain proportion of an organic drug molecule will ionize at a given pH. The smaller the frac-tion of total drug molecules ionized, the weaker the electrolyte. Since most drugs are either weak organic acids or bases (i.e., weak electrolytes), their degree of ionization will influence their lipid–water partition co-efficient and hence their ability to diffuse through mem-branes.
The proportion of the total drug concentration that is present in either ionized or un-ionized form is dic-tated by the drug’s dissociation or ionization constant (K) and the local pH of the solution in which the drug is dissolved.
The dissociation of a weak acid, RH, and a weak base, B, is described by the following equations:
If these equations are rewritten in terms of their dis-sociation constants (using Ka for both weak acids and weak bases), we obtain
By taking logarithms and then substituting the terms pK and pH for the negative logarithms of Ka and [H+ ], respectively, we arrive at the Henderson-Hasselbach equations:
It is customary to describe the dissociation constants of both acids and bases in terms of pKa values. This is possible in aqueous biological systems because a simple mathematical relationship exists between pKa, pKb, and the dissociation constant of water pKw
The use of only pKa values to describe the relative strengths of either weak bases or weak acids makes comparisons between drugs simpler. The lower the pKa value (pKa< 6) of an acidic drug, the stronger the acid (i.e., the larger the proportion of ionized molecules). The higher the pKa value (pKa > 8) of a basic drug, the stronger the base. Thus, knowing the pH of the aqueous medium in which the drug is dissolved and the pKa of the drug, one can, using the Henderson-Hasselbach equation, calculate the relative proportions of ionized and un-ionized drug present in solution. For example, when the pKa of the drug (e.g., 7) is the same as the pH (e.g., 7) of the surrounding medium, there will be equal proportions of ionized [R-1 and un-ionized [RH] mole-cules; that is, 50% of the drug is ionized.
The effect of pH on drug ionization is shown in Figure 3.3. The relationship between pH and degree of drug ion-ization is not linear but sigmoidal; that is, small changes in pH may greatly influence the degree of drug ionization, especially when pH and pKa values are initially similar.