Accumulation of furancarboxylic acids in uremic serum as inhibitors of drug binding

Niwa, Toshimitsu; Takeda, Nobuhiro; Maeda, Kenji; Shibata, Masao; Tatematsu, Akira

doi:10.1016/0009-8981(88)90250-1

Cited by 62 publications

(39 citation statements)

References 13 publications

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“…For example, a glucuronide of 3-carboxy-4-methyl-5-pentyl-2-furanpropionic acid, a known uremic retention solute shown to inhibit the binding of salicylate and 5,5-diphenylhydantoin to albumin (46), was identified exclusively in the serum of conv animals. The greatly increased concentrations of this furan dicarboxylic acid, as well as other classic uremic retention solutes such as indoxyl sulfate, p-cresol sulfate, urate, and hippuric acid in the blood of these animals, point to the large burden that the metabolic processes of enteric bacteria impose on the chemical detoxification mechanism of their hosts.…”

Section: Other Phase II Metabolic Products Are Also Greatly Elevated Inmentioning

confidence: 99%

Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites

Wikoff

Anfora²,

Li³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

2,295

1,878

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Although it has long been recognized that the enteric community of bacteria that inhabit the human distal intestinal track broadly impacts human health, the biochemical details that underlie these effects remain largely undefined. Here, we report a broad MS-based metabolomics study that demonstrates a surprisingly large effect of the gut ''microbiome'' on mammalian blood metabolites. Plasma extracts from germ-free mice were compared with samples from conventional (conv) animals by using various MS-based methods. Hundreds of features were detected in only 1 sample set, with the majority of these being unique to the conv animals, whereas Ϸ10% of all features observed in both sample sets showed significant changes in their relative signal intensity. Amino acid metabolites were particularly affected. For example, the bacterial-mediated production of bioactive indole-containing metabolites derived from tryptophan such as indoxyl sulfate and the antioxidant indole-3-propionic acid (IPA) was impacted. Production of IPA was shown to be completely dependent on the presence of gut microflora and could be established by colonization with the bacterium Clostridium sporogenes. Multiple organic acids containing phenyl groups were also greatly increased in the presence of gut microbes. A broad, drug-like phase II metabolic response of the host to metabolites generated by the microbiome was observed, suggesting that the gut microflora has a direct impact on the drug metabolism capacity of the host. Together, these results suggest a significant interplay between bacterial and mammalian metabolism.

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Section: Other Phase II Metabolic Products Are Also Greatly Elevated Inmentioning

confidence: 99%

Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites

Wikoff

Anfora²,

Li³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

2,295

1,878

View full text Add to dashboard Cite

show abstract

“…Two slices were placed in each flask and the medium (which consisted of rinse medium, 10 mM L-lactate, and 10 mM L-pyruvate) in each flask was thoroughly gassed with 100% oxygen for about 1 min both before and after the addition of the slices. A concentration of 20 M was chosen for the substrate (CMPF) because this is the concentration normally found in healthy humans (Niwa et al, 1988). The flasks were then tightly sealed with rubber stoppers and incubated in a shaking water bath at 60 cycles/min for 60 min at 25°C.…”

Section: Methodsmentioning

confidence: 99%

“…Since these initial reports, it has also been reported to accumulate in uremic plasma, reaching concentrations in the range of 60 to 370 M (Niwa et al, 1988). In addition, a growing body of evidence suggests that it is a significant uremic toxin (Niwa, 1996).…”

mentioning

confidence: 99%

Renal Disposition of a Furan Dicarboxylic Acid and Other Uremic Toxins in the Rat

Tsutsumi¹,

Deguchi²,

Takano³

et al. 2002

J Pharmacol Exp Ther

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The aim of this study was to understand the mechanisms that underlie the renal elimination of albumin-bound uremic toxins, particularly the highly bound furan acid 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), that accumulate in chronic renal failure. These toxins inhibit the binding of acidic drugs and have various other untoward effects. The pharmacokinetics and tissue distribution of CMPF plus three other such toxins, indoxyl sulfate, indole acetic acid, and hippuric acid, have been examined in the anesthetized rat. The effects of p-aminohippuric (PAH) acid and tetraethylammonium on the uptake of CMPF by rat renal cortical slices in vitro were also investigated to characterize its mechanism of uptake. Plasma and tissue concentrations of the uremic toxins were determined by high-performance liquid chromatography. The rate of elimination of the toxins from plasma was indoxyl sulfate Ͼ hippuric acid Ͼ indole acetic acid Ͼ CMPF. Although the renal clearance of CMPF was low, its main elimination pathway was via urinary excretion with active tubular secretion. In renal cortical slice experiments, mutual inhibition between CMPF and PAH was observed. In addition, ␣-ketoglutarate stimulated the uptake of CMPF by renal cortical slices. The base tetraethylammonium did not inhibit slice uptake of CMPF. The pharmacokinetics of CMPF was characterized by slow plasma clearance and localization in the kidney. Furthermore, the evidence from experiments with renal cortical slices indicates that the uptake of CMPF is mediated by an anion/dicarboxylate exchanger, similar to that for PAH.

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“…Although CMPF has been implicated in the anemia which occurs in chronic renal failure [2], in irregularities of thyroid function [3], in neurological symptoms which may be caused by the inhibition of organic anion transport at the blood-brain barrier [4], and in inhibition of mitochondrial respiration [5], its pharmacokinetic properties or toxicity remains unclear. Many workers have focused on the serum protein binding of CMPF [1, 6]because of its high affinity for human serum albumin (HSA). CMPF is not removed by hemodialysis, …”

Section: Introductionmentioning

confidence: 99%

Decreased Bilirubin-Binding Capacity in Uremic Serum Caused by an Accumulation of Furan Dicarboxylic Acid

Tsutsumi

Maruyama

Takadate

et al. 2000

Nephron

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In chronic renal failure, substances that are effectively excreted in healthy subjects accumulate in serum. These substances, uremic toxins, include a variety of organic acids. It has been reported that a decrease in the bilirubin (BR) binding capacity occurs in the serum of renal failure patients. 3-Carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) has a high affinity for human serum albumin (HSA) and is a potent inhibitor of the serum protein binding of many drugs. We recently reported that CMPF and BR share the binding site for dicarboxylate molecules on the HSA molecule [Pharm Res 1999;16:916–923]. In this study, in order to confirm whether CMPF is involved in the decrease of BR serum binding capacity in chronic renal failure patients, the total concentrations of uremic toxins, CMPF, and indoxyl sulfate (IS) and the free BR concentration in serum from healthy volunteers and renal failure patients were determined. Both total CMPF and IS concentrations correlate with the free BR concentration. However, results from the peroxidase method reveal that IS cannot displace BR under the physiological condition [IS]/[HSA] <1. We, therefore, conclude that CMPF is one of the substances which contribute to the decreased binding capacity of BR in uremic serum.

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Accumulation of furancarboxylic acids in uremic serum as inhibitors of drug binding

Cited by 62 publications

References 13 publications

Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites

Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites

Renal Disposition of a Furan Dicarboxylic Acid and Other Uremic Toxins in the Rat

Decreased Bilirubin-Binding Capacity in Uremic Serum Caused by an Accumulation of Furan Dicarboxylic Acid

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