Penicillins, serum binding

Nevertheless, it was necessary to give three equations with different constants for penicillins with an a-amino or a-ether group in the side-chain, or with an ortho aromatic ether group (methicillin analogues). It was suggested that the mechanism involves hydrophobic binding and /3-lactam antibiotics are able to bind to serum when ionic sites for this are not available, e.g. the case of penicillin amides, cephalosporin lactones (Table 8.9) and certain 2-substituted cephalosporins (Table 8.7), when the increased lipophilicity leads to increased serum binding. 

Bird, A. E., Marshall, A. C. Correlation of serum binding of penicillins with partition coefficients. Biochem. Pharmacol. 16, 2275 (1967). 

Penicillins and cephalosporins bind irreversibly to serum albumin. It has been shown that drug-protein conjugates result from the aminolysis of the /3-lactam bond by the e-amino group of lysine residues in the protein (Fig. 5.1, Pathway e). The bound penicilloyl group appears to be the major antigenic determinant of penicillin allergy [145-148],... 

In neonates drugs such as various penicillins, pheno-barbital, phenytoin, and theophylline have lower protein-binding affinity than in adults. This may increase the concentration of free or pharmacological active drug in neonates, and may also change the apparent volume of distribution. Thus, neonates may require different doses on a mg/kg basis compared to that for adults for these drugs to achieve appropriate therapeutic serum concentrations. 

Penicillin + probenecid Threefold increase in serum penicillin level with increase also in spinal fluid levels but decreased brain level Displacement from protein binding, decreased renal tubule secretion and decrease biliary excretion Combination can be used when high serum and spinal fluid levels are required... 

Partitioning between butyl acetate and aqueous acidic and basic solutions has been used as a separation procedure by many investigators, e.g., 64, 65. Bethel and Bond 64 extract penicillin V acid into butanol,and the salt back into aqueous phosphate buffer. Such procedures are found in many of the papers describing analytical methods. In studies correlating serum protein binding with partition coefficients, the log of the n-octanol-water partition coefficient for phenoxymethyl penicillin (free acid) is given 66 as 2.09 and the distribution coefficient between silicone oil and water was determined 67. 

Binding of drugs, including penicillin V, with plasma proteins has been reviewed recently 133, 134 Studies correlating serum protein binding with partition coefficients were summarized in section 5.2. 

The P-lactam antibiotics continued to be the cynosure of synthesis. Some structure-activity relationships of peni-cillins O and cephalosporins 2 v/ere discussed. Timely reports aimed primarily toward the evaluation of the newer highly serum-bound penicillins dealt with the controversial relationship of drug-serum protein binding to clinical antimicrobial effectiveness. 3,14... 

Terasaki, T. Nouda, H. Tsuji, A. Relationship between lipophilicity and binding affinity with human serum albumin for penicillin and cephem antibiotics. J.Pharmacobiodyn., 1992, IS, 99—106... 

Kunin CM. Clinical pharmacology of the new penicillins. II. Effect of drugs which interfere with binding to serum proteins. Clin Pharmacol Ther (1966) 7, 180-88. 

Albumin is a protein polypeptide. Albumin has a molecular weight of 66.5 kDa and is the most abundant plasma protein, which is present in the concentration of 35-50 g/L in human serum and is synthesized in the liver. Human serum albumin (HSA) has a half-life of 19 days. It acts as a solubilizing agent for long chain fatty acids and is therefore essential for the transport and metabolism of lipids. It binds very well to penicillins, sulfonamides, indole compounds, benzodiazepines, copper, and nickel in a specific and calcium and zinc in a relatively nonspecific manner. It is responsible for osmotic pressure of the blood. 

---