Effects of Uremic Toxins on the Binding of Aripiprazole to Human Serum Albumin

• Published in: Biological & pharmaceutical bulletin Vol. 44; no. 3; pp. 437 - 441
• Main Authors: Nishi, Koji, Sakurama, Keiki, Watanabe, Hiroshi, Maruyama, Toru, Yamasaki, Keishi, Otagiri, Masaki
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01.03.2021; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: Albumin; Antipsychotics; Aripiprazole; Binding sites; Circular dichroism; Diazepam; Equilibrium dialysis; Human serum albumin; Indoleacetic acid; Pharmacokinetics; protein binding; Sulfates; Toxins; uremic toxin; aripiprazole; uremic toxin; protein binding; human serum albumin
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b20-00929

We recently reported that aripiprazole (ARP), an antipsychotic drug, binds strongly to human serum albumin (HSA), the major drug binding protein in serum. It is known that uremic toxins that accumulate during renal disease affect the interaction between HSA and drug binding. In this study, the issue of how uremic toxins (indoxyl sulfate, indole acetic acid and p-cresyl sulfate) affect the binding of ARP to HSA was investigated. Equilibrium dialysis experiments revealed that all uremic toxins inhibited the binding of ARP to HSA although the inhibitory effects differed, depending on the specific uremic toxin. The potency of inhibition can be partially explained by the affinities of uremic toxins to HSA. Fluorescence displacement experiments suggested that ARP as well as all uremic toxins bind to site II of HSA. The inhibitory effects of the toxins on the binding of ARP for the drugs binding to the diazepam subsite are significantly larger, comparing with those for binding to arylpropionic acids subsite. Interestingly, induced circular dichroism (CD) spectra indicated that the spatial orientation of p-cresyl sulfate in the binding pocket is different from that for indoxyl sulfate and indole acetic acid. The limited findings obtained herein are important data in considering the effects of uremic toxins on the pharmacokinetics of ARP and the drugs that bind to site II on HSA, particularly drugs binding to diazepam binding site in site II.