Kitamura Keisuke, Takegami Shigehiko, Tanaka Rumi, Omran Ahmed Ahmed, Kitade Tatsuya
Kyoto Pharmaceutical University, 5 Nakauchicho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
Chemistry Department, Faculty of Science, Al-Azhar University, Assiut 71524, Egypt. ; Chemistry Department, Faculty of Science, King Khalid University, Abha 9004, Saudi Arabia.
Sci Pharm. 2013 Dec 28;82(2):233-45. doi: 10.3797/scipharm.1310-23. Print 2014 Apr-Jun.
Human serum albumin (HSA) in the blood binds long-chain fatty acids (LCFAs), and the number of bound LCFAs varies from 1 to 7 depending on the physical condition of the body. In this study, the influence of LCFA-HSA binding on drug-HSA binding was studied using triflupromazine (TFZ), a psychotropic phenothiazine drug, in a buffer (0.1 M NaCl, pH 7.40, 37°C) by a second-derivative spectrophotometric method which can suppress the residual background signal effects of HSA observed in the absorption spectra. The examined LCFAs were caprylic acid (CPA), lauric acid (LRA), oleic acid (OLA), and linoleic acid (LNA), respectively. Using the derivative intensity change of TFZ induced by the addition of HSA containing LCFA, the binding mode of TFZ was predicted to be a partition-like nonspecific binding. The binding constant (K M(-1)) showed an increase according to the LCFA content in HSA for LRA, OLA, and LNA up to an LCFA/HSA molar ratio of 3-4. However, at higher ratios the K value decreased, i.e. for OLA and LNA, at an LCFA/HSA ratio of 6-7, the K value decreased to 40% of the value for HSA alone. In contrast, CPA, having the shortest chain length (8 carbons) among the studied LCFAs, induced a 20% decrease in the K value regardless of its content in HSA. Since the pharmacological activity of a drug is closely related to the unbound drug concentration in the blood, the results of the present study are pharmaco-kinetically, pharmacologically, and clinically very important.
血液中的人血清白蛋白（HSA）会结合长链脂肪酸（LCFA），结合的LCFA数量因身体状况而异，从1到7不等。在本研究中，使用精神类吩噻嗪药物三氟拉嗪（TFZ），在缓冲液（0.1M NaCl，pH 7.40，37°C）中，通过二阶导数分光光度法研究了LCFA - HSA结合对药物 - HSA结合的影响，该方法可以抑制在吸收光谱中观察到的HSA残留背景信号效应。所检测的LCFA分别为辛酸（CPA）、月桂酸（LRA）、油酸（OLA）和亚油酸（LNA）。利用添加含LCFA的HSA后诱导的TFZ导数强度变化，预测TFZ的结合模式为类似分配的非特异性结合。对于LRA、OLA和LNA，结合常数（K M(-1)）随着HSA中LCFA含量的增加而增加，直至LCFA/HSA摩尔比达到3 - 4。然而，在更高的比例下，K值会降低，即对于OLA和LNA，在LCFA/HSA比例为6 - 7时，K值降至仅HSA时的40%。相比之下，在所研究的LCFA中链长最短（8个碳）的CPA，无论其在HSA中的含量如何，都会使K值降低20%。由于药物的药理活性与血液中未结合药物的浓度密切相关，本研究结果在药代动力学、药理学和临床上都非常重要。
