Relationship between Lipophilicity and Binding Affinity with Human Serum Albumin for Penicillin and Cephem Antibiotics

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Relationship between structure and binding affinity to human serum albumin (HSA) has been studied for penicillin and cephem antibiotics. For penicillin analogs, a good correlation between the apparent affinity constants, K_<app>, for HSA binding and the partition coefficient, P_<app>, determined in isobutyl alcohol-pH 7.4 phosphate buffer system was observed, indicating that the hydrophobic interaction of 6-substituent of penicillins with amino acid of HSA would play and important role for the binding. However, no correlation between the K_<app> and P_<app> values was observed for cephem antibiotics. Mutual competitive displacement effects were demonstrated for the primary binding sites of cephalothin, cefazolin, cefotetan and cefatrizine, suggesting the presence of a common binding region in HSA among these cephem antibiotics examined. Significant differences were observed for the K_<app> value among cephems having the same 3-substitute of N-methylthiotetrazole in the molecule, i.e., cefpiramide, cefotetan, cefoperazone, cefamandole, cefmenoxime, cefmetazole and cefbuperazone, suggesting that 7-substitute of cephem would play an important role for the binding with HSA. Moreover, comparing the binding affinity and the structure of 3-substitute for cephems, all of the analogs having a heterocycle bind strongly with HSA in spite of their low lipophilicity. These observations suggest that an interaction between heterocycle at the position 3 and HSA would contribute to an additional binding force for the binding of cephem antibiotics to HSA.
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Relationship between Lipophilicity and Binding Affinity with Human Serum Albumin for Penicillin and Cephem Antibiotics

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