Interaction of Aripiprazole With Human α 1 -Acid Glycoprotein

We recently reported that aripiprazole binds strongly to human albumin. In continuing our investigations, we investigated the mechanism responsible for the binding and the related interactions of aripiprazole with α1-acid glycoprotein (AGP). The extrinsic Cotton effects for the binding of aripiprazo...

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Bibliographic Details
Published inJournal of pharmaceutical sciences Vol. 108; no. 12; p. 3911
Main Authors Nishi, Koji, Sakurama, Keiki, Kobashigawa, Yoshihiro, Morioka, Hiroshi, Udo, Nagiko, Hashimoto, Mai, Imoto, Shuhei, Yamasaki, Keishi, Otagiri, Masaki
Format Journal Article
LanguageEnglish
Published United States 01.12.2019
Subjects
human albumin
drug binding
α-acid glycoprotein
binding mode
ITC method
aripiprazole
plasma protein
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Summary:We recently reported that aripiprazole binds strongly to human albumin. In continuing our investigations, we investigated the mechanism responsible for the binding and the related interactions of aripiprazole with α1-acid glycoprotein (AGP). The extrinsic Cotton effects for the binding of aripiprazole and its derivatives to AGP were generated, but the magnitudes of the induced circular dichroism intensities did not correlate with those for the binding affinities. It therefore appears that the binding mode of aripiprazole with AGP is somewhat complicated, compared with that of albumin. Isothermal titration calorimetry data obtained for the binding of aripiprazole with AGP were different from that for albumin systems in that the 3 driving reactions, entropy-driven, enthalpy-driven, and the entropy-enthalpy mixed type, were all found for the AGP system, but not albumin. Moreover, the weak binding mode of aripiprazole with the 2 proteins were supported by a molecular docking model analysis. The concentration of albumin in plasma is about 50 times higher than those of AGP, but AGP levels in plasma are increased by about 10 times under inflammatory disease. Therefore, the involvement of these 2 plasma proteins should be considered in more depth for understanding the pharmacokinetics of aripiprazole.
ISSN:1520-6017