Interaction of Aripiprazole with Human α1-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 aripiprazole and its derivatives to AGP were generated but the magnitudes of the induced CD intensities did not correlate with the 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 (ITC) data obtained for the binding of aripiprazole with AGP were different from that for albumin systems in that the three 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 two 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 two plasma proteins should be considered in more depth for understanding the pharmacokinetics of aripiprazole.