The Binding of Antibiotics to Serum Proteins

Abstract

The published work on the binding of antibiotics to serum proteins is extensive. Nevertheless, data are still incomplete in certain respects. For example, there is little information on the rate at which antibiotics are bound to the proteins and the rate at which this complex breaks down. Similarly, although the binding of antibiotics to serum proteins is known to be essentially reversible it is not certain whether there is any proportion of the drug which is bound irreversibly. On certain aspects, published data are available but are conflicting and some lack of agreement exists on the precise extent of binding of certain antibiotics, particularly of tetracyclines. There is also a general lack of comparative results on the extent of binding for related antibiotics obtained from experiments carried out by the same method.In the present paper, results are given for the effect of certain factors on the binding of penicillins and other antibiotics in serum and comparative data are also given for the extent of binding in human serum for all the penicillins at present in clinical use. METHODS Measurement of binding of antibiotics to serum proteinsThe extent of binding of penicillins and other antibiotics to the proteins of serum was measured by ultrafiltration through Visking viscose-cellulose dialysis tubing. Preliminary experiments indicated that there was no significant difference between the extent of binding in plasma obtained from heparinized blood and that in serum. The antibiotic present in the protein-free ultrafiltrate was measured by microbiological assay and this quantity represented the free, unbound, fraction of antibiotic in serum. The amount of antibiotic bound to protein was derived by subtracting the level of free antibiotic from the known total concentration in serum. Before comparative experiments were made to measure the extent to which different antibiotics were bound to the proteins of human serum, preliminary investigations were carried out into the effects of various experimental factors thought likely to influence the extent of binding. These included the effects of antibiotic concentration, nature of protein, temperature, individual variation, rate of binding and nature of binding. Ultrafiltraton techniquesSuitable lengths of Visking tubing (0.25 in. internal diameter) were knotted at one end and attached at the other to a manifold connected to compressed air. Serum samples were introduced into the tubing before connexion to the manifold and ultrafiltration was then carried out at room temperature at a positive pressure of 15 lb/in2. The ultrafiltrate was collected in a glass tube which closely surrounded the Visking sac. In most experiments the volume of serum used was 5 ml., and the volume of ultrafiltrate collected for assay was about 0.5 ml. In some experiments a volume of 10 to 12 ml. of serum was used which permitted an adequate sample of ultrafiltrate to be collected in about 7 min. ANTIBIOTICS AND SERUM PROTEINS 639Horse, sheep, rabbit, and calf sera were obtained as commercial samp...

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