Further Evidence Regarding the Important Role of Chlorine Atoms of Aripiprazole on Binding to the Site II Area of Human Albumin

Keiki Sakurama, Koji Nishi, Shuhei Imoto, Mai Hashimoto, Teruyuki Komatsu, Yoshitsugu Morita, Kazuaki Taguchi, Masaki Otagiri, Keishi Yamasaki

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Abstract

Previously, we reported on the high-affinity binding of aripiprazole (ARP), an antipsychotic drug, to human albumin and the role of the chlorine atom of ARP on this binding. In this study, we investigated the binding mode of ARP to human albumin in detail using ARP derivatives and several animal-derived albumins. ARP bound strongly to human and dog albumin. The circular dichroism (CD) spectra of ARP bound to human and dog albumin were also similar. Deschloro-ARP bound less strongly to all of the albumin species compared to ARP, and the shapes of CD spectra were similar for all albumin species. CD spectra of dimethyl-ARP, for which chlorine atoms were substituted methyl groups, were quite similar to that of deschloro-ARP. In displacement experiments, competitive binding was observed between ARP and deschloro-ARP. These results suggest that the chlorine atoms in ARP are involved in the binding modes of ARP for human and dog albumins, whereas ARP and deschloro-ARP appear to share the same binding region in site II. The aforementioned results imply that compounds having a chlorine atom bind more strongly to plasma proteins, resulting in a long blood retention time. Therefore, findings reported here may provide the basically useful data for drug design.

Original languageEnglish
JournalJournal of Pharmaceutical Sciences
DOIs
Publication statusAccepted/In press - 2019 Jan 1

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Keywords

  • albumin species
  • aripiprazole
  • chlorine atom
  • drug binding
  • human albumin

ASJC Scopus subject areas

  • Pharmaceutical Science

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