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

Abstract

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.

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

“…We recently investigated the effects of uremic toxins and albumin oxidation (using chloramine-T) on ARP binding [5,6]. The inhibitory effect of ARP binding by IS (80% increase in the free fraction) was more significant than that by oxidation (40% increase in the free fraction) [5].…”

“…We also investigated the effects of uremic toxins on the binding of ARP to human albumin. Uremic toxins such as indoxyl sulphate (IS), indole 3-acetic acid, and pcresyl sulphate (PCS), particularly IS and PCS, inhibited the binding of ARP to albumin [6]. We then attempted to elucidate the molecular mechanism responsible for the interaction of ARP with plasma proteins in kidney diseases, based upon relationships between ARP albumin binding and biochemical parameters such as the plasma concentrations of albumin, oxidized albumin and uremic toxins.…”

Zeolite Composite Nanofiber Mesh for Indoxyl Sulfate Adsorption toward Wearable Blood Purification Devices

“…Specifically, hemodialysis is capable of removing IS at a rate of 25 to 30 mL/min, which is only 10% of the clearance for free and small uremic toxins in urea [6]. Approximately 90% of IS in serum is bound to albumin, and these large bound particles cannot pass through the dialysis membrane [7]. IS can reportedly accelerate the progression of CKD [8,9] and induce cardiovascular disease, osteoporosis, and anemia [10,11].…”