Reaction of ampicillin with serum albumin to produce penicilloyl-protein conjugates and a piperazinedione

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Abstract
Formation of penicilloyl-protein conjugates in the body by reaction of penicillins with nucleophilic groups of proteins is considered to be involved in penicillin allergy. In this study the kinetics and mechanism of reaction of ampicillin with human and bovine serum albumin in aqueous solution at 37 °C and pH 6.6–10.4 have been investigated and compared with the reaction of benzylpenicillin previously reported. In addition to forming penicilloyl-protein conjugates, ampicillin was found to react with the proteins to yield a free piperazine-2,5-dione derivative. This product is suggested to arise from intramolecular aminolysis of an N-(penicilloyl)imidazole intermediate at pH 6–8 and of a penicilloyl ester intermediate at higher pH values. The piperazinedione formation was found to compete effectively with formation of penicilloyl-protein conjugates at physiological pH and, along with studies of ampicillin with protein model compounds, the reaction allowed suggestions to be made about the penicillin-reacting sites in the proteins.