Analysis of the Binding of Aripiprazole to Human Serum Albumin: The Importance of a Chloro-Group in the Chemical Structure

Sakurama, Keiki; Kawai, Akito; Chuang, Victor Tuan Giam; Kanamori, Yoko; Osa, Miyu; Taguchi, Kazuaki; Seo, Hakaru; Maruyama, Toru; Imoto, Shuhei; Yamasaki, Keishi; Otagiri, Masaki

doi:10.1021/acsomega.8b02057

Cited by 25 publications

(31 citation statements)

References 36 publications

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“…PhthaloNH 2 has a rigid structure and is extended in two dimensions, compared to other compounds that have a longitudinally extended appearance and possibly have elements of flexibility, allowing them to bend. Analyzing other reports in the literature, in which albumin has been co-crystallized with longitudinal-looking ligands or having flexible elements, deep binding of phthaloNH 2 to Sudlow’s site I is difficult due to its size and rigidity [ 36 , 37 ].…”

Section: Resultsmentioning

confidence: 99%

Fluorescent Phthalocyanine-Encapsulated Bovine Serum Albumin Nanoparticles: Their Deployment as Therapeutic Agents in the NIR Region

et al. 2021

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In recent times, researchers have aimed for new strategies to combat cancer by the implementation of nanotechnologies in biomedical applications. This work focuses on developing protein-based nanoparticles loaded with a newly synthesized NIR emitting and absorbing phthalocyanine dye, with photodynamic and photothermal properties. More precisely, we synthesized highly reproducible bovine serum albumin-based nanoparticles (75% particle yield) through a two-step protocol and successfully encapsulated the NIR active photosensitizer agent, achieving a good loading efficiency of 91%. Making use of molecular docking simulations, we confirm that the NIR photosensitizer is well protected within the nanoparticles, docked in site I of the albumin molecule. Encouraging results were obtained for our nanoparticles towards biomedical use, thanks to their negatively charged surface (−13.6 ± 0.5 mV) and hydrodynamic diameter (25.06 ± 0.62 nm), favorable for benefitting from the enhanced permeability and retention effect; moreover, the MTT viability assay upholds the good biocompatibility of our NIR active nanoparticles. Finally, upon irradiation with an NIR 785 nm laser, the dual phototherapeutic effect of our NIR fluorescent nanoparticles was highlighted by their excellent light-to-heat conversion performance (photothermal conversion efficiency 20%) and good photothermal and size stability, supporting their further implementation as fluorescent therapeutic agents in biomedical applications.

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Section: Resultsmentioning

confidence: 99%

Fluorescent Phthalocyanine-Encapsulated Bovine Serum Albumin Nanoparticles: Their Deployment as Therapeutic Agents in the NIR Region

et al. 2021

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“…IS was detected using a fluorescence monitor with excitation/emission wavelengths set to 280 and 375 nm, respectively. Plasma ARP concentration was measured by HPLC, as described previously [2]. The HPLC system used in this study consisted of a 655 A-11 pump, 655 A variable wavelength UV monitor (Hitachi Co., Ltd., Tokyo, Japan).…”

Section: Equilibrium Dialysismentioning

confidence: 99%

“…We recently reported that aripiprazole (ARP), 7-(4-(4-(2,3-dichloropheny)-1-piperazinyl) buthoxy)-3,4-dihydro-2-(1H)-quinolinone, a novel antipsychotic agent, binds strongly to two major plasma proteins, namely, human albumin and α1-acid glycoprotein [2,3]. ARP is effective, especially in long-term use.…”

Section: Introductionmentioning

confidence: 99%

The Binding of Aripiprazole to Plasma Proteins in Chronic Renal Failure Patients

Hirata

Ikeda

Watanabe

et al. 2021

Toxins

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The binding of drugs to plasma protein is frequently altered in certain types of renal diseases. We recently reported on the effects of oxidation and uremic toxins on the binding of aripiprazole (ARP) to human serum albumin. In our continuing investigations, we examined the binding of ARP to plasma pooled from patients with chronic renal dysfunction. We examined the issue of the molecular basis for which factors affect the changes in drug binding that accompany renal failure. The study was based on the statistical relationships between ARP albumin binding and biochemical parameters such as the concentrations of oxidized albumin and uremic toxins. The binding of ARP to plasma from chronic renal patients was significantly lower than healthy volunteers. A rational relationship between the ARP binding rate and the concentration of toxins, including indoxyl sulphate (IS) and p-cresyl sulphate (PCS), was found, particularly for IS. Moreover, multiple regression analyses that involved taking other parameters such as PCS or oxidized albumin ratio to IS into account supports the above hypothesis. In conclusion, the limited data reported in this present study indicates that monitoring IS in the blood is a very important determinant in the dosage plan for the administration of site II drugs such as ARP, if the efficacy of the drug in renal disease is to be considered.

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“…In fact, Ikeda et al made the misleading conclusion that the binding of furosemide to bovine serum albumin is competitively inhibited by indoxyl sulfate, which is one of the typical uremic toxins. 7) To clarify this issue, systematic inhibitory experiments using uremic toxins that bind tightly to HSA should be done.…”

Section: Introductionmentioning

confidence: 99%

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

Nishi

Sakurama

Watanabe

et al. 2021

Biological & Pharmaceutical Bulletin

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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.

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Analysis of the Binding of Aripiprazole to Human Serum Albumin: The Importance of a Chloro-Group in the Chemical Structure

Cited by 25 publications

References 36 publications

Fluorescent Phthalocyanine-Encapsulated Bovine Serum Albumin Nanoparticles: Their Deployment as Therapeutic Agents in the NIR Region

Fluorescent Phthalocyanine-Encapsulated Bovine Serum Albumin Nanoparticles: Their Deployment as Therapeutic Agents in the NIR Region

The Binding of Aripiprazole to Plasma Proteins in Chronic Renal Failure Patients

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

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