Species‐dependent stereoselective drug binding to albumin: A circular dichroism study

Abstract

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.

Study of relative stability of tautomeric forms of phenylbutazone and calculation of UV-Vis and ECD spectra

“…No entanto, toda a análise espectroscópica foi feita na forma enolato, pois vários das resultados experimentais são obtidos em pH básico pH fisiológico). 8,9 Na forma aniônica da fenilbutazona observa-se uma maior planaridade do anel de cinco membros (Fig. 2), contrariamente à forma protonada.…”

“…Já a nossa estratégia é puramente baseada na varredura relaxada ao longo de ângulos diedros preferenciais (discutida adiante), e (c) e nosso interesse está na análise espectroscópica da forma do enolato (forma aniônica da fenilbutazona), pois vários das resultados experimentais são obtidos em pH básico (pH fisiológico). 8,9 A presença de um plano de simetria na molécula de fenilbutazona, na forma cetônica confere à mesma a propriedade de girar o plano da luz plano polarizada. Assim, é possível utilizar informações de espectros de dicroísmo circular eletrônico (ECD) para caracterizar aspectos de sua estrutura molecular.…”

Protein Binding of Antimicrobials: Methods for Quantification and for Investigation of its Impact on Bacterial Killing

“…In this approach, concentrations of albumin usually around 5% are used, which widely excludes factors hampering bacterial growth (9). Similar to serum, due to interspecies differences in binding affinities for antibiotics, human albumin appears most representative for human in vivo conditions (66). An albumin concentration of 4 g/dL is widely used, as this is equivalent to the albumin concentration in human serum (7,46,47,49,62,67).…”

Binding of licarbazepine enantiomers to mouse and human plasma proteins

“…In the sequence of recent noticeable differences found in the biodisposition of S-Lic and R-Lic after their separate administration to mice [25], it becomes necessary to clarify the contribution of plasma protein binding to this phenomenon. This study was designed to determine the binding of Lic enantiomers to mouse and human plasma proteins and, then, to the main plasma proteins involved in the binding of drugs, human serum albumin (HSA) [26,27] and a 1 -acid glycoprotein (AGP) [28].…”