Pistolozzi Marco, Bertucci Carlo
Department of Pharmaceutical Sciences, University of Bologna, Italy.
Chirality. 2008 Mar;20(3-4):552-8. doi: 10.1002/chir.20521.
Drug binding to albumins from different mammalian species was investigated to disclose evidence of species-dependent stereoselectivity in drug-binding processes and affinities. This aspect is important for evaluating the reliability of extrapolating distribution data among species. The circular dichroism (CD) signal induced by drug binding to the albumins [human serum albumin (HSA), bovine serum albumin (BSA), rat serum albumin (RSA), and dog serum albumin (DSA)] were measured and analyzed. The binding of selected drugs and metabolites to HSA significantly differed from the binding to the other albumins in terms of affinity and conformation of the bound ligands. In particular, phenylbutazone, a marker of site one on HSA, showed a higher affinity for binding to BSA with respect to RSA, HSA, and DSA, respectively. In the case of diazepam, a marker of site two on HSA, the affinity decreased in order from HSA to DSA, RSA, and BSA. The induced CD spectra were similar in terms of energy and band signs, suggesting almost the same conformation for the bound drug to the different albumins. Stereoselectivity was high for the binding of ketoprofen to HSA and RSA. A different sign was observed for the CD spectra induced by the drug to the two albumins because of the prevalence of a different conformation of the bound drug. Interestingly, the same induced CD spectra were obtained using either the racemic form or the (S)-enantiomer. Finally, significant differences were observed in the affinity of bilirubin, being highest for BSA, then decreasing for RSA, HSA, and DSA. A more complex conformational equilibrium was observed for bound bilirubin.
研究了药物与不同哺乳动物物种白蛋白的结合情况，以揭示药物结合过程和亲和力中物种依赖性立体选择性的证据。这一方面对于评估物种间分布数据外推的可靠性很重要。测量并分析了药物与白蛋白[人血清白蛋白（HSA）、牛血清白蛋白（BSA）、大鼠血清白蛋白（RSA）和狗血清白蛋白（DSA）]结合所诱导的圆二色性（CD）信号。所选药物和代谢物与HSA的结合在亲和力和结合配体的构象方面与与其他白蛋白的结合有显著差异。特别是，HSA上位点一的标志物保泰松，相对于RSA、HSA和DSA，对与BSA的结合表现出更高的亲和力。对于HSA上位点二的标志物地西泮，亲和力从HSA到DSA、RSA和BSA依次降低。诱导的CD光谱在能量和谱带符号方面相似，表明结合到不同白蛋白上的药物构象几乎相同。酮洛芬与HSA和RSA结合的立体选择性较高。由于结合药物构象的不同占优势，药物诱导的两种白蛋白的CD光谱观察到不同的符号。有趣的是，使用外消旋体或（S）-对映体获得了相同的诱导CD光谱。最后，观察到胆红素亲和力存在显著差异，对BSA最高，然后对RSA、HSA和DSA降低。观察到结合胆红素存在更复杂的构象平衡。
