In passive transport, the drug molecule usually penetrates by diffusion along a concentration gradient by virtue of its solubility in the lipid bilayer. Such transfer is directly proportional to the magnitude of the concentration gradient across the membrane, to the lipid-water partition coefficient of the drug, and to the membrane surface area exposed to the drug. After a steady state is attained, the concentration of the unbound drug is the same on both sides of the membrane if the drug is a nonelectrolyte. For ionic compounds, the steady-state concentrations depend on the electrochemical gradient for the ion and on differences in pH across the membrane, which may influence the state of ionization of the molecule disparately on either side of the membrane.
WEAK ELECTROLYTES AND INFLUENCE OF pH Most drugs are weak acids or bases that are present in solution as both the lipid-soluble and diffusible nonionized form, and the relatively lipid-insoluble nondiffusible ionized species. Therefore, the transmembrane distribution of a weak electrolyte is determined by its pKa (pH at which 50% is ionized) and the pH gradient across the membrane (see Figure 1-2). The ratio of nonionized to ionized drug at each pH is readily calculated from the Henderson-Hasselbalch equation:
This equation relates the pH of the medium around the drug and the drug's acid dissociation constant (pKa) to the ratio of the protonated (HA or BH+) and unprotonated (A- or B) forms, where HA ^ A- + H+ (Ka = [A-][H+]/[HA]) describes the dissociation of an acid, and BH+ ^ B + H+ (K = [B][H+]/[BH+]) describes the dissociation of the pronated form of a base. At steady state, an acidic drug will accumulate on the more basic side of the membrane and a basic drug on the more acidic side—a phenomenon termed ion trapping.
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