Keire D A, Mariappan S V, Peng J, Rabenstein D L
Department of Chemistry, University of California, Riverside 92521.
Biochem Pharmacol. 1993 Sep 14;46(6):1059-69. doi: 10.1016/0006-2952(93)90671-i.
The metabolism of the thiol-containing drugs penicillamine (beta,beta-dimethylcysteine) and captopril (D-3-mercapto-2-methylpropanoyl-L-proline) involves the formation of mixed disulfides, including mixed disulfides with serum albumin. The reactions of penicillamine and captopril with serum albumin in aqueous solution and in intact human blood plasma have been studied by 500 MHz 1H NMR spectroscopy. Penicillamine was found to react rapidly at the albumin-cysteine mixed disulfide bond to form penicillamine-cysteine mixed disulfide and to react more slowly at other albumin disulfide bonds. The amino acid cysteine was found to react with albumin by the same two pathways. In contrast, captopril rapidly associates with albumin to form noncovalent albumin-captopril complexes. Exchange of captopril between its free and noncovalently bound forms takes place on the NMR time scale. On a longer time scale, captopril reacts with albumin by thiol/disulfide interchange reactions. Noncovalently bound captopril displaced lactate from its albumin binding sites, both in aqueous solution and in human plasma. The results demonstrate that 1H NMR is a useful method for characterizing the state of drug molecules in human plasma and for detecting and monitoring perturbations by drugs of delicately balanced binding equilibria involving endogenous small molecules and macromolecules in plasma.
含硫醇药物青霉胺（β，β - 二甲基半胱氨酸）和卡托普利（D - 3 - 巯基 - 2 - 甲基丙酰 - L - 脯氨酸）的代谢涉及混合二硫键的形成，包括与血清白蛋白形成的混合二硫键。已通过500 MHz 1H NMR光谱研究了青霉胺和卡托普利在水溶液和完整人血浆中与血清白蛋白的反应。发现青霉胺在白蛋白 - 半胱氨酸混合二硫键处迅速反应形成青霉胺 - 半胱氨酸混合二硫键，而在其他白蛋白二硫键处反应较慢。发现氨基酸半胱氨酸通过相同的两条途径与白蛋白反应。相比之下，卡托普利迅速与白蛋白结合形成非共价的白蛋白 - 卡托普利复合物。卡托普利在其游离形式和非共价结合形式之间的交换发生在NMR时间尺度上。在更长的时间尺度上，卡托普利通过硫醇/二硫键交换反应与白蛋白反应。在水溶液和人血浆中，非共价结合的卡托普利都从其白蛋白结合位点取代了乳酸。结果表明，1H NMR是表征人血浆中药物分子状态以及检测和监测药物对涉及血浆中内源性小分子和大分子的微妙平衡结合平衡的扰动的有用方法。
