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

Kenshiro Hirata,Victor Chuang,Masaki Otagiri,Yuji Uchida,Hiroshi Watanabe,Keishi Yamasaki,Keiki Sakurama,Toru Maruyama,Tokunori Ikeda,Motoko Tanaka,Koji Nishi

doi:10.3390/toxins13110811

Kenshiro Hirata, Victor Chuang + Show 9 more

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https://doi.org/10.3390/toxins13110811

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Abstract

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.

Highlights

Patients with impaired renal function are prone to demonstrate a high incidence of adverse drug reactions
We investigated the effects of uremic toxins on the binding of ARP to human albumin
We previously reported that ARP, a novel antipsychotic agent, binds to albumin

Summary

Introduction

Patients with impaired renal function are prone to demonstrate a high incidence of adverse drug reactions. It is generally assumed that such a high adverse drug reaction rate is mainly due to the accumulation of the drug in the body as the result of a decreased kidney excretion. It is well known that the plasma binding capacity of many drugs is lower in uremic patients than in normal subjects, even after correction for the below-average albumin concentration in these patients. At a relatively lower total plasma drug concentration than would occur for a nonuremic patient [1]. For drugs with excellent central transfer properties such as ARP, it is assumed that the effect of an increase in the concentration of the unbound form in the body would have a significant effect on its action

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