ABSTRACT
The transport of drugs is governed by diffusion, surface area available for transfer, lipid solubility, molecular weight, degree of ionization, partition coefficient, and maternal-fetal concentration gradient. The availability of a drug for transport is dependent, in turn, on the binding of the drug to the plasma proteins. Forming a drug-protein complex is contingent upon covalent and ionic bonding between polar and nonpolar groups on the antibiotic and upon the polarity of amino acids available for binding. The unbound fraction in the serum is pharmacologically active and in a state of dynamic equilibrium with the drug present in the extra-cellular space. As free drug is excreted or metabolized, protein-bound drug is released so as to maintain a relatively constant proportion of free drug. Serum protein levels do not influence the eventual utilization of all of the drug present in the plasma, but rather determine the amount of free drug available at any given moment. Only the unbound drug passes freely across membranes separating biologic compartments. It is this form of the drug which is capable of antimicrobial action. The affinity of plasma proteins for a specific drug is not necessarily indicative of its binding capacity. Certain carrier proteins may have a high affinity for a given drug but a relatively low binding capacity. When the binding sites are saturated, a secondary plasma protein usually participates in the reaction, even though its binding affinity is lower. Different drugs may compete for the same binding site on a protein molecule. The unbound plasma levels will be increased if the bound form on a protein molecule is displaced by another drug with a greater affinity for that particular binding site. Once the free form of the drug has entered into a given biologic compartment, such as the fetal intravascular space or the amniotic fluid, it is again subjected to the binding ratios of those proteins present. The lack of a significant amount of protein in certain biologic compartments such as the cerebrospinal fluid (CSF) and amniotic fluid may account for the relative efficiency of certain drugs in eradicating bacteria, despite the low concentrations achieved relative to those in the corresponding vascular compartment. The significance of protein binding is brought into sharp focus when therapy is initiated for the fetus rather than the mother. Because of its protein binding, the distribution of ampicillin is such that it is often the drug of choice in terms of first-line fetal therapeutics.
