Stereoselective binding of chiral drugs to plasma proteins

Abstract

Chiral drugs show distinct biochemical and pharmacological behaviors in the human body. The binding of chiral drugs to plasma proteins usually exhibits stereoselectivity, which has a far-reaching influence on their pharmacological activities and pharmacokinetic profiles. In this review, the stereoselective binding of chiral drugs to human serum albumin (HSA), α1-acid glycoprotein (AGP) and lipoprotein, three most important proteins in human plasma, are detailed. Furthermore, the application of AGP variants and recombinant fragments of HSA for studying enantiomer binding properties is also discussed. Apart from the stereoselectivity of enantiomer-protein binding, enantiomer-enantiomer interactions that may induce allosteric effects are also described. Additionally, the techniques and methods used to determine drug-protein binding parameters are briefly reviewed.

Human vascular model with defined stimulation medium – a characterization study

“…In serum-free conditions we detected thinner and more branched tubules as also reported by Yang and Xiong (Yang and Xiong, 2012). Serum-free medium is ideal for use in drug development, since serum is a complex mixture of components with unknown composition and protein binding affinities (Shen et al, 2013). Furthermore, a tissue construct aimed for clinical therapy should be cultured in human serum or, preferably, in a serum-free environment to avoid the risk of infection and severe immune reactions in the recipient (Patrikoski et al, 2013;Lindroos et al, 2011Lindroos et al, , 2010Holm et al, 2010).…”

“…In addition, the developmental stage of the model system and a defined medium composition are critical, especially when toxicological applications are considered. Serum-free medium with xeno-free and defined supplements is considered essential for in vitro models to decrease the variation between experiments due to unknown components in the medium, and further, unknown binding properties of these components (Shen et al, 2013;Brunner et al, 2010;van der Valk et al, 2010). Currently, culture media are still commonly supplemented with serum, although it has a highly uncharacterized composition, including various cytokines and growth factors, as well as a lot-to-lot variability (Lindroos et al, 2011;Brunner et al, 2010).…”

ABSOLUTE CONFIGURATION ASSIGNMENT IN RACEMIC trans-STILBENE OXIDE USING CHIRAL LIQUID CHROMATOGRAPHY WITH COMBINED CHIROPTICAL DETECTION AND TIME-DEPENDENT DENSITY FUNCTIONAL THEORY CALCULATIONS

“…1 Conventional methods often involve complex procedures or require milligrams of high-purity samples, as is the case for chemical correlation, single-crystal X-ray diffraction, 2 or electronic/vibrational circular dichroism spectroscopies. 3 Methods based on chiroptical phenomena 3 can clearly be more useful when coupled to chromatographic techniques, such as HPLC, enabling measurement of these properties in smaller and more complex samples and therefore extending their applicability.…”

Automated synthesis and PET evaluation of both enantiomers of [18F]FMISO

“…Several factors may cause such differences. In particular, binding to tissue and plasma proteins, primarily to albumin, as well as to lipoproteins and red blood cells can be stereoselective [11,12]. As this binding affects the plasma concentration of free drug, this could in turn affect the rates of excretion and degradation and ultimately plasma half-life and biodistribution.…”