Effect of Long-Chain Fatty Acids on the Binding of Triflupromazine to Human Serum Albumin: A Spectrophotometric Study

Abstract

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.

The impact of the concentration of drug binding plasma proteins on drug distribution according to Øie-Tozer’s model

“…To design this model to accurately describe this phenomenon appears very difficult. However, investigations into the connection between the dissociation constant for the drug-serum albumin complex and fatty acid additions reveals that the k d versus fatty acid content per serum albumin can be quite linear at lower fatty acid loadings as exemplified for triflupromazine (Kitamura et al, 2013). Thus, the identified linear pattern can be mathematically captured by assuming that all fatty acids aggregate with serum albumin to generate a complex between serum albumin and four fatty acids.…”

Strategies for developing long-lasting therapeutic nucleic acid aptamer targeting circulating protein: The present and the future

“…Human serum albumin (HSA) is a protein abundantly present in human plasma (about 40 mg/ml) ( Kitamura et al, 2014 ), which has a high binding affinity to various drugs. It has a molecular weight of 67 kDa and an attractive biological half-life of about 19 days ( Hijazi, 2021 ).…”