Durham University, Department of Chemistry, South Road, Durham, DH1 3LE, UK.
Anal Chem. 2012 Mar 6;84(5):2299-304. doi: 10.1021/ac2029425. Epub 2012 Feb 9.
The investigation of chiral interactions of drugs with plasma proteins is of fundamental importance for drug efficacy and toxicity studies. In this paper, we demonstrate a simple liquid-liquid interface procedure for investigating chiral interactions. Chiral discrimination of the enantiomers of a basic drug, propranolol, was achieved at a micro liquid-liquid interface, using α(1)-acid-glycoprotein (AGP) as a chiral acute phase plasma protein. When the protein is added to an aqueous phase containing the enantiomers of propranalol hydrochloride, the binding of (S)- and (R)-propranolol hydrochloride to the protein results in a decrease in the cyclic voltammetry (CV) and differential pulse voltammetry (DPV) current responses corresponding to the decrease in transfer of propranolol at an aqueous-1,2-dichloroethane interface. This decrease is a consequence of the complexation of the drug and the protein. The complex drug-protein does not transfer across the interface nor changes the transfer potential of the uncomplexed form of propranolol enantiomers. The bound concentration of propranolol enantiomers in the presence of AGP was found to be greater for (S)-propranolol than (R)-propranolol for solutions containing constant concentrations of AGP (50 μM). Scatchard analysis yielded association constants of 2.7 and 1.3 × 10(5) M(-1) for (S)- and (R)-propranolol, respectively.
研究药物与血浆蛋白之间的手性相互作用对于药物疗效和毒性研究至关重要。在本文中，我们展示了一种简单的液-液界面方法来研究手性相互作用。在手性药物盐酸普萘洛尔的对映体的微液-液界面处，使用α(1)-酸性糖蛋白(AGP)作为手性急性相血浆蛋白，实现了对映体的手性区分。当将蛋白质加入含有盐酸普萘洛尔对映体的水相时，(S)-和(R)-盐酸普萘洛尔与蛋白质的结合导致对应于在水-1,2-二氯乙烷界面处普萘洛尔传递减少的循环伏安法(CV)和差分脉冲伏安法(DPV)电流响应减小。这种减少是由于药物和蛋白质的络合。复合物药物-蛋白质不会穿过界面，也不会改变未络合形式的普萘洛尔对映体的传递电位。在含有 AGP 的溶液中，发现与 AGP 存在时的 (S)-普萘洛尔比 (R)-普萘洛尔的结合浓度更高，AGP 的浓度为 50 μM。Scatchard 分析得到 (S)-和 (R)-普萘洛尔的结合常数分别为 2.7 和 1.3×10(5) M(-1)。
