Tawara S, Matsumoto S, Matsumoto Y, Kamimura T, Goto S
New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
J Antibiot (Tokyo). 1992 Aug;45(8):1346-57. doi: 10.7164/antibiotics.45.1346.
The binding of some cephalosporins to human serum albumin (HSA) was studied by an ultrafiltration technique. Changes in C-3 side chain resulted in marked changes in the binding to HSA, but changes in C-7 side chain did not. Cephalosporins were classified into three groups by C-3 side chain: (i) Cationic side chain with low affinity for HSA; (ii) anionic side chain with high affinity for HSA; (iii) non ionized side chain, in which binding to HSA was dependent on lipophilicity. These findings suggest that electrostatic and hydrophobic forces play a role in the binding affinity of cephalosporins for HSA. The binding of cephalosporins with high HSA affinity was displaced significantly by warfarin but not by phenylbutazone, L-tryptophan, or diazepam. The interaction of the cephalosporins with high affinity for HSA with chemically modified HSA was investigated to clarify the amino acid residues of HSA involved in the cephalosporin binding sites. The binding of the cephalosporins decreased remarkably with the modification of the tyrosine residues. These results suggest that the binding site of cephalosporins is located in the vicinity of warfarin binding site rather than benzodiazepine binding site and that tyrosine residues are involved in the cephalosporin binding site.
采用超滤技术研究了某些头孢菌素与人血清白蛋白（HSA）的结合情况。C-3侧链的变化导致与HSA结合的显著变化，但C-7侧链的变化则不然。根据C-3侧链，头孢菌素可分为三组：（i）对HSA亲和力低的阳离子侧链；（ii）对HSA亲和力高的阴离子侧链；（iii）非离子化侧链，其与HSA的结合取决于亲脂性。这些发现表明，静电和疏水力在头孢菌素与HSA的结合亲和力中起作用。对华法林有高HSA亲和力的头孢菌素的结合被华法林显著取代，但未被保泰松、L-色氨酸或地西泮取代。研究了对HSA有高亲和力的头孢菌素与化学修饰的HSA的相互作用，以阐明参与头孢菌素结合位点的HSA的氨基酸残基。随着酪氨酸残基的修饰，头孢菌素的结合显著降低。这些结果表明，头孢菌素的结合位点位于华法林结合位点附近而非苯二氮䓬结合位点，且酪氨酸残基参与了头孢菌素结合位点。
