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© 2017 The Pharmaceutical Society of Japan. A high dietary intake of phosphorus is considered to be a significant health threat for hemodialysis (HD) patients. Prescription medications, which might be a major source of phosphorus, is largely unrecognized in Japan. However, the amount of phosphorus indicated on the package label, is not quantified. In this study, the phosphorus content of 22 of the most widely prescribed medications that are used in conjunction with HD therapy were examined and differences between branded and generic prescription medications were compared. All samples were selected from medications that are typically prescribed for HD patients. The samples were ground prior to analysis. Phosphorus was measured using the Wako L-Type Phosphate method. All instruments used in the study were calibrated according to the manufacturers' specifications. Amlodipine (15 mg/tablet) and paroxetine (30.0 mg/tablet) were found to contain higher contents of phosphorus than the medications tested. Differences in phosphorus content between branded and generic drugs was also determined. The phosphorus content of all generic paroxetine preparations was significantly lower than the values for identical branded medications. On the other hand, the phosphorus content of several generic amlodipine preparations were significantly different from those of similar, branded preparations. Specific information regarding the phosphorus content of prescribed medications used by HD patient needs to be made available to the dialysis community.

During pasteurization and storage of albumin products, Sodium octanoate (Oct) and N-acethyl-l-tryptophan (N-AcTrp) are used as the thermal stabilizer and the antioxidant for human serum albumin (HSA), respectively. We recently reported that N-acethyl-l-methionine (N-AcMet) is an antioxidant for HSA, which is superior to N-AcTrp when it is especially exposed to light during storage. The objective of the present study is to clarify the molecular mechanism responsible for the HSA protective effect of Oct and N-AcMet based on their ternary complex structure. Crystal structure of the HSA-Oct-N-AcMet complex showed that one N-AcMet molecule is bound to the entrance of drug site 1 of HSA, and its side chain, which is susceptible to the oxidation, is exposed to the solvent. At the same time, two Oct binding sites are observed in drug sites 1 and 2 of HSA, respectively, and each Oct molecule occupies the hydrophobic cavity in them. These results indicate the molecular mechanism responsible for the HSA stabilization by these small molecules as follows. N-AcMet seals the entrance of drug site 1 while it acts as an antioxidant for HSA. Oct is chiefly bound to drug site 2 of HSA and it increases the thermal stability of HSA because of the occupying the largest intra-cavity of sub-domain IIIA in HSA. These findings suggest that N-AcMet acts positively as useful stabilizer for albumin formulated products such as functionalized HSA and HSA fusion proteins.

Objectives The half-life of fatty acid-conjugated antidiabetic drugs are prolonged through binding to albumin, but this may not occur in diabetic patients with nephropathy complicated with hypoalbuminemia. We previously showed that human serum albumin (HSA) dimerized at the protein's Cys34 by 1,6-bis(maleimido)hexane has longer half-life than the monomer under high permeability conditions. The aim of this study was to investigate the superior ability of this HSA dimer as a plasma-retaining agent for fatty acid conjugated antidiabetic drugs. Methods The diabetic nephropathy rat model was prepared by administering a single injection of streptozotocin (STZ) intravenously, and the pharmacokinetic properties of HSA monomer and dimer were evaluated. Site-specific fluorescent probe displacement experiments were performed using warfarin and dansylsarcosine as site I and site II specific fluorescent probes, respectively. Key findings The half-life of the HSA dimer in STZ-induced diabetic nephropathy model rats was 1.5 times longer than the HSA monomer. The fluorescent probe displacement experiment results for HSA monomer and dimer were similar, where fatty acid-conjugated antidiabetic drugs displaced dansylsarcosine but not warfarin in a concentration-dependent manner. Conclusions The HSA dimer shows potential for use as a plasma-retaining agent for antidiabetic drugs due to its favourable pharmacokinetic properties.

Curcuminoids are a group of compounds with a similar chemical backbone structure but containing different numbers of methoxy groups that have therapeutic potential due to their anti-inflammatory and anti-oxidant properties. They mainly bind to albumin in plasma. These findings influence their body disposition and biological activities. Spectroscopic analysis using site specific probes on human serum albumin (HSA) clearly indicated that curcumin (Cur), demethylcurcumin (Dmc) and bisdemethoxycurcumin (Bdmc) bind to both Site I (sub-site Ia and Ib) and Site II on HSA. At pH 7.4, the binding constants for Site I were relatively comparable between curcuminoids, while the binding constants for Site II at pH 7.4 were increased in order Cur , Dmc , Bdmc. Binding experiments using HSA mutants showed that Trp214 and Arg218 at Site I, and Tyr411 and Arg410 at Site II are involved in the binding of curcuminoids. The molecular docking of all curcuminoids to the Site I pocket showed that curcuminoids stacked with Phe211 and Trp214, and interacted with hydrophobic and aromatic amino acid residues. In contrast, each curcuminoid interacted with Site II in a different manner depending whether a methoxy group was present or absent. A detailed analysis of curcuminoids-albumin interactions would provide valuable information in terms of understanding the pharmacokinetics and the biological activities of this class of compounds.

The degree of oxidized cysteine (Cys) 34 in human serum albumin (HSA), as determined by high performance liquid chromatography (HPLC), is correlated with oxidative stress related pathological conditions. In order to further characterize the oxidation of Cys34-HSA at the molecular level and to develop a suitable analytical method for a rapid and sensitive clinical laboratory analysis, the use of electrospray ionization time-of-flight mass spectrometer (ESI-TOFMS) was evaluated. A marked increase in the cysteinylation of Cys34 occurs in chronic liver and kidney diseases and diabetes mellitus. A significant positive correlation was observed between the Cys-Cys34-HSA fraction of plasma samples obtained from 229 patients, as determined by ESI-TOFMS, and the degree of oxidized Cys34-HSA determined by HPLC. The Cys-Cys34-HSA fraction was significantly increased with the progression of liver cirrhosis, and was reduced by branched chain amino acids (BCAA) treatment. The changes in the Cys-Cys34-HSA fraction were significantly correlated with the alternations of the plasma levels of advanced oxidized protein products, an oxidative stress marker for proteins. The binding ability of endogenous substances (bilirubin and tryptophan) and drugs (warfarin and diazepam) to HSA purified from chronic liver disease patients were significantly suppressed but significantly improved by BCAA supplementation. Interestingly, the changes in this physiological function of HSA in chronic liver disease were correlated with the Cys-Cys34-HSA fraction. In conclusion, ESI-TOFMS is a suitable high throughput method for the rapid and sensitive quantification of Cys-Cys34-HSA in a large number of samples for evaluating oxidative stress related chronic disease progression or in response to a treatment.

Background: Oxidative damage results in protein modification, and is observed in numerous diseases. Human serum albumin (HSA), the most abundant circulating protein in the plasma, exerts important antioxidant activities against oxidative damage. Scope of Review: The present review focuses on the characterization of chemical changes in HSA that are induced by oxidative damage, their relevance to human pathology and the most recent advances in clinical applications. Major Conclusions: The antioxidant properties of HSA are largely dependent on Cys34 and its contribution to the maintenance of intravascular homeostasis, including protecting the vascular endothelium under disease conditions related to oxidative stress. Recent studies also evaluated the susceptibility of other important amino acid residues to free radicals. The findings suggest that a redox change in HSA is related to the oxidation of several amino acid residues by different oxidants. Further, Cys34 adducts, such as S-nitrosylated and S-guanylated forms also play an important role in clinical applications. On the other hand, the ratio of the oxidized form to the normal form of albumin (HMA/HNA), which is a function of the redox states of Cys34, could serve as a useful marker for evaluating systemic redox states, which would be useful for the evaluation of disease progression and therapeutic efficacy. General Significance: This review provides new insights into our current understanding of the mechanism of HSA oxidation, based on in vitro and in vivo studies.