Absorption, Distribution and Excretion
19.2 ± 3.3 L. …Although the pattern of volatile organic compounds (VOCs) in exhaled breath varies in patients with obstructive sleep apnea (OSA), individual VOC profiles are not fully defined. The primary endpoint was the characterization of VOCs; secondary endpoints included the relationship between VOCs and sleep and clinical parameters in OSA patients. We prospectively performed full polysomnography on 32 OSA patients with an apnea-hypopnea index (AHI) ≥15 and included a control group of 33 age- and sex-matched patients without significant OSA symptoms. Nine patients with severe OSA underwent examination before and after continuous positive airway pressure (CPAP) therapy. Using a method to eliminate the influence of environmental VOCs, we identified VOCs in exhaled breath using gas chromatography-mass spectrometry (GC-MS) and determined their concentrations using GC. The concentrations of exhaled aromatic hydrocarbons (toluene, ethylbenzene, p-xylene, and phenylacetic acid) in the severe obstructive sleep apnea (OSA) group (AHI ≥ 30) and the concentrations of exhaled saturated hydrocarbons (hexane, heptane, octane, nonane, and decane) in the most severe OSA group (AHI ≥ 60) were higher than in the control group. Exhaled isoprene concentrations were elevated in all OSA groups (AHI ≥ 15); exhaled acetone concentrations were elevated in the most severe OSA group. Concentrations of ethylbenzene, p-xylene, phenylacetic acid, and nonane increased with increasing OSA severity and were correlated with AHI, arousal index, and duration of transcutaneous oxygen saturation (SpO2) ≤ 90%. Multivariate regression analysis showed that the concentrations of these four volatile organic compounds (VOCs) were correlated with the duration of SpO2 ≤ 90%. Isoprene and acetone levels decreased after CPAP treatment. OSA increases the production of certain toxic VOCs, some of which are associated with OSA severity. CPAP treatment may improve the production of these VOCs.
In a phase I clinical trial, researchers conducted dose-limiting toxicity and pharmacokinetics studies of phenylacetic acid (phenylacetate) in 17 patients with advanced solid tumors. These patients received a single intravenous bolus followed by continuous intravenous infusion over 14 days. Phenylacetic acid exhibited nonlinear pharmacokinetic characteristics, and there was evidence that drug clearance was induced. 99% of phenylacetic acid is eliminated via conversion to phenylacetylglutamine, which is excreted in the urine…
Phenylacetic acid…is rapidly absorbed by human oral tissues or mucous membranes.
93% is excreted in the form of glutamine conjugates…New World monkeys excrete conjugates of glutamine, glycine, and taurine, while Old World monkeys excrete large amounts of free acid as well as conjugates of glutamine and taurine. Non-primates excrete only glycine conjugates.
The distribution of conjugates in 24-hour urine samples showed significant species differences.
Metabolism/Metabolites
Phenylacetase is present in the cytoplasm of human hepatocytes. Human plasma esterases can also hydrolyze phenylacetic acid. The hydrolysis of phenylacetic acid involves aryl esterases in plasma, aryl esterases and carboxylesterases in liver microsomes, and carboxylesterases in hepatic cytoplasm. Plasma hydrolysis is weaker, and overall esterase activity in humans is lower than in rats. Despite growing interest in high-protein diets, little is known about dietary protein-related metabolomic changes in mammals. We investigated the effects of protein intake on specific tryptophan and phenolic compounds derived from endogenous and colonic microbial metabolism. Furthermore, we investigated potential interspecies metabolic differences. To this end, we randomly assigned 29 healthy subjects to either a high-protein group (n = 14) or a low-protein group (n = 15) for 2 weeks. Additionally, we randomly assigned 20 wild-type FVB mice to either a high-protein group or a control group for 21 days. Plasma and urine samples were analyzed using liquid chromatography-mass spectrometry to determine tryptophan and phenolic metabolites. In human subjects, we observed significant changes in plasma indole sulfate levels and urinary excretion (P < 0.004 and P < 0.001), as well as significant changes in urinary excretion of indole glucuronic acid (P < 0.01), kynurenic acid (P < 0.006), and quinolinic acid (P < 0.02). In mice, there were significant differences in plasma tryptophan (P < 0.03), indole-3-acetic acid (P < 0.02), p-cresol glucuronic acid (P < 0.03), phenyl sulfate (P < 0.004), and phenylacetic acid (P < 0.01). Therefore, dietary protein intake affects the plasma levels and production of various mammalian metabolites, suggesting its influence on both endogenous and colonic microbial metabolism. The differences in metabolite changes between humans and mice indicate metabolic differences in protein intake among different species.
Burkholderia PAK1-2, isolated from the rhizosphere of rice, is an effective biocontrol agent for preventing bacterial wilt disease in rice seedlings caused by Burkholderia phytohelia. In this study, a non-antimicrobial metabolite was isolated from B. heleia PAK1-2 culture medium. This metabolite inhibited the virulence of B. plantarii and was identified as indole-3-acetic acid (IAA). IAA inhibited the production of tyrosine in B. plantarii in a dose-dependent manner and did not exhibit antimicrobial or quorum sensing inhibitory activity, indicating that IAA inhibited the biosynthetic step of tyrosine. Consistent with this, the addition of L-[cyclo-(2)H5]phenylalanine or [cyclo-(2)H2~5]phenylacetic acid to the B. plantarii culture medium revealed that phenylacetic acid (PAA)—a major metabolite in the early growth stages—is a direct precursor of tyrosine. IAA treatment inhibited the production of both PAA and tyrosine in B. plantarii. These data specifically indicate that the IAA produced by B. heleia PAK1-2 interferes with the formation of tyrosine during the biotransformation of PAA to tyrosine through rearrangement on the precursor benzene ring, thereby weakening the toxicity of B. plantarii. Therefore, B. heleia PAK1-2 is likely a bacterium that coordinates the microbial community in the rhizosphere ecosystem; it does not eliminate plant pathogens but only inhibits the production of plant toxins or bactericides. 2-Phenylethylamine is an endogenous component of the human brain and is involved in brain signaling. This bioactive amine is also present in some foods, such as chocolate, cheese, and wine, and may cause adverse side effects in susceptible individuals. The metabolism of 2-phenylethylamine to phenylacetaldehyde is mainly catalyzed by monoamine oxidase B, but the oxidation to phenylacetaldehyde is usually attributed to aldehyde dehydrogenase, while the roles of aldehyde oxidase and xanthine oxidase (if any) are neglected. This study aims to elucidate the roles of molybdenum hydroxylase, aldehyde oxidase, and xanthine oxidase in the metabolism of phenylacetaldehyde. We treated 2-phenylethylamine with monoamine oxidase to produce phenylacetaldehyde, and then treated synthetically produced or enzymatically generated phenylacetaldehyde with aldehyde oxidase, xanthine oxidase, and aldehyde dehydrogenase. The results showed that phenylacetaldehyde was mainly metabolized to phenylacetic acid by these three oxidases, with a small amount of 2-phenylethanol produced. Aldehyde dehydrogenase is the main enzyme in the oxidation of phenylacetaldehyde and therefore plays an important role in the metabolism of 2-phenylethylamine, while the role of aldehyde oxidase is relatively minor. Since the content of xanthine oxidase in guinea pigs is low, it does not participate in the oxidation of phenylacetaldehyde. This indicates that aldehyde dehydrogenase is not the only enzyme oxidizing exogenous and endogenous aldehydes, and the role of aldehyde oxidase in these reactions cannot be ignored. The main metabolite of phenylethylamine, phenylacetic acid, was identified and quantified in the rat brain region by high-resolution gas chromatography-mass spectrometry using capillary column. Its distribution was heterogeneous and correlated with the distribution of phenylethylamine. The obtained values (ng/g ± SEM) were: whole brain, 31.2 ± 2.7; caudate nucleus, 64.6 ± 6.5; hypothalamus, 60.1 ± 7.4; cerebellum, 31.3 ± 2.9; brainstem, 33.1 ± 3.3; other parts, 27.6 ± 3.0. For more complete metabolite/metabolite data on phenylacetic acid (9 metabolites in total), please visit the HSDB record page. 2-Phenylacetic acid is a known human metabolite of 4-hydroxyphenylacetic acid and 3-hydroxyphenylacetic acid. Uremic toxins often accumulate in the blood due to overeating or poor kidney filtration. Most uremic toxins are metabolic waste products and are usually excreted through urine or feces.

Toxicity Summary
Identification and Uses: Phenylacetic acid is a white to yellow crystal or flake. It is used in perfumes, as a precursor to penicillin G, as a bactericide, flavoring agent, and laboratory reagent. It is also used in the manufacture of drugs of abuse. Human Studies: Inhalation causes cough and sore throat. Skin contact causes erythema. Eye contact causes erythema and pain. Animal Studies: Acute oral toxicity is low in rats. In acute effects studies in mice, intraperitoneal injection of 300 mg/kg phenylacetic acid was toxic. No tumor formation was observed in rabbits after intravenous and subcutaneous injection of phenylacetic acid for 40 days. In vitro studies have shown that concentrations of phenylacetic acid above 0.3 mg/mL induce dose-related embryotoxicity. In teratogenicity studies in rats, administration of 3.2 mg/kg phenylacetic acid on day 12 of embryonic development affected body weight, delayed bone ossification, and doubled embryonic resorption rate compared to the control group. Phenylacetic acid inhibits coenzyme A activity. Uremic toxins (such as phenylacetic acid) can be actively transported to the kidneys via organic ion transporters, especially OAT3. Elevated levels of uremic toxins can stimulate the production of reactive oxygen species (ROS). This appears to be mediated by the direct binding of uremic toxins to or inhibition of NADPH oxidases, particularly NOX4, which is abundant in the kidneys and heart (A7868). ROS can induce a variety of different DNA methyltransferases (DNMTs) involved in the silencing of KLOTHO protein. KLOTHO has been shown to play an important role in anti-aging, mineral metabolism, and vitamin D metabolism. Multiple studies have shown that in acute or chronic kidney disease, KLOTHO mRNA and protein levels are reduced due to elevated local ROS levels (A7869).

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Non-human toxicity values
Oral LD50 in rats: 2250 mg/kg
Oral LD50 in mice: 2250 mg/kg
Subcutaneous LD50 in mice: 1500 mg/kg
Intraperitoneal LD50 in mice: 2270 mg/kg
For more non-human toxicity values (complete data) for phenylacetic acid (6 out of 6), please visit the HSDB record page.

Phenylacetic acid is a monocarboxylic acid formed by replacing a hydrogen atom on the methyl group of a toluene molecule with a carboxyl group. It has multiple functions, including acting as a toxin, a human metabolite, an E. coli metabolite, a plant metabolite, a Saccharomyces cerevisiae metabolite, an EC 6.4.1.1 (pyruvate carboxylase) inhibitor, an Aspergillus metabolite, a plant growth inhibitor, an allergen, and an auxin. It is a monocarboxylic acid belonging to the benzene and phenylacetic acid groups. Its function is related to acetic acid, and it is the conjugate acid of phenylacetic acid esters. Phenylacetic acid is an organic compound containing phenyl and carboxylic acid functional groups; it is a white solid with an unpleasant odor. Because phenylacetic acid is used in the illicit production of acetone (used to manufacture substituted amphetamines), it is regulated in several countries, including the United States and China. Phenylacetic acid is a metabolite of E. coli (K12 strain, MG1655 strain). Phenylacetic acid is a nitrogen-binding agent. Its mechanism of action is as an ammonium ion binder. Phenylacetic acid has been reported to exist in Biscogniauxia mediterranea, Penicillium herquei, and other organisms with relevant data. Phenylacetic acid is a uremic toxin. Based on chemical and physical properties, uremic toxins can be classified into three main categories: 1) small, water-soluble, non-protein-bound compounds, such as urea; 2) small molecule, lipid-soluble compounds and/or protein-bound compounds, such as phenolic compounds; and 3) larger, so-called medium-molecule compounds, such as β2-microglobulin. Long-term exposure to uremic toxins can lead to various diseases, including kidney damage, chronic kidney disease, and cardiovascular disease. Phenylacetate (or phenylacetic acid) is a carboxylic acid ester that has been found in the body fluids of patients with nephritis and/or hepatitis, as well as patients with phenylketonuria (PKU). Excess phenylalanine in the body can be excreted through transamination to form phenylpyruvic acid. Phenyruvic acid can be further metabolized into various products. Phenyruvic acid undergoes decarboxylation to form phenylacetate, which is then reduced to form phenyllactic acid. Phenylacetyl acetate can further combine with glutamine to form phenylacetylglutamine. These metabolites can be detected in the serum and urine of patients with phenylketonuria (PKU). Phenylacetyl acetate can also be produced endogenously as a metabolite of 2-phenylethylamine, which is mainly metabolized by monoamine oxidase to phenylacetyl acetate. 2-Phenylethylamine is an endogenous amphetamine that may regulate central adrenergic function, and the level of phenylacetyl acetate in urine has been considered a marker of depression. Phenylacetyl acetate is also found in essential oils, such as neroli oil, rose oil (in free and ester forms), and in many fruits. Therefore, it is used as a flavoring and flavoring agent. (1, 2, 3). Phenylacetyl acetate is a metabolite found or produced in Saccharomyces cerevisiae.
Pharmacological Indications
Used as adjunctive therapy for acute hyperammonemia and related encephalopathy in patients with urea cycle enzyme deficiency.

C8H8O2

136.15

136.05

103-82-2

114-70-5 (hydrochloride salt);13005-36-2 (potassium salt);52009-49-1 (calcium salt);7188-16-1 (ammonium salt)

999

Leaflets on distillation in-vacuo; plates, tablets from petroleum ether
Shiny, white plate crystals
White to yellow crystals or flakes

76.7 °C
76.7 °C
76.5 °C

1.4

1

2

2

10

114

0

WLJVXDMOQOGPHL-UHFFFAOYSA-N

InChI=1S/C8H8O2/c9-8(10)6-7-4-2-1-3-5-7/h1-5H,6H2,(H,9,10)

2-phenylacetic acid

Benzylcarboxylic acid; Benzeneacetic acid; Phenylacetic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)