Sulfate Metabolites Research Articles

A Pharmacokinetic Study of the Interaction Between Regorafenib and Paracetamol in Male Rats

Background: In clinical practice, the prevalent problem of polypharmacy could result in increased risks of drug–drug interactions. Regorafenib (REG) is commonly co-administered with paracetamol (PA) as a treatment protocol in cancer patients with pain therapy. Purpose: This study aimed to demonstrate the effect of paracetamol on the pharmacokinetic parameters of regorafenib and its metabolites following a single administration of both substances in rats. Additionally, the influence of REG and its metabolites on the pharmacokinetics of paracetamol was also determined. Methods: Twenty-four rats were divided randomly into three groups: REG group (IIREG, regorafenib 20 mg/kg, n = 8), PA group (IIIPA, paracetamol 100 mg/kg, n = 8), and REG+PA co-administration group (IREG+PA, REG 20 mg/kg and PA 100 mg/kg, n = 8). The concentrations of regorafenib, regorafenib-N-oxide (M-2), and N-desmethyl-regorafenib-N-oxide (M-5) were determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC–MS/MS). The plasma concentrations of PA and its glucuronide (GPA) and sulfate (SPA) metabolites were measured using the validated high-performance liquid chromatography method with ultraviolet detection (HPLC–UV). The pharmacokinetic parameters were calculated using a non-compartmental model. The statistical evaluation was performed in the SAS program. Results: After the administration of PA, the Cmax and AUC0–∞ of REG increased by 890% and 1140%, respectively; for M-2, they increased by 220% and 170%, and for M-5, by 2130% and 1730% (Cmax and AUC0–∞, respectively). A difference in the ratio of M-2/REG for AUC0–∞ and Cmax between the groups was observed, but not for M-5/REG. The AUC0–∞ for PA and GPA decreased by 20.7% and 51.1%, respectively, when PA was co-administered with REG. But the AUC0–∞ for SPA increased by 91.35% in the IREG+PA group. A difference in the ratio of GPA/PA for Cmax and for SPA/PA for AUC0–t and AUC0–∞ between the groups was observed. Conclusions: Paracetamol increased the plasma exposure of regorafenib, M-2, and M-5, which may exacerbate the drug’s side effects. In contrast, REG reduced paracetamol exposure and contributed to its faster elimination, which may reduce the analgesic and antipyretic effects of paracetamol. These findings suggest clinical relevance for oncology patients requiring analgesic treatment.

Interaction of myricetin, ampelopsin (dihydromyricetin), and their sulfate metabolites with serum albumin, cytochrome P450 (CYP2C9, 2C19, and 3A4) enzymes, and organic anion-transporting polypeptides (OATP1B1 and OATP2B1).

Myricetin (MYR) and ampelopsin (AMP, or dihydromyricetin) are flavonoid aglycones found in certain plants and dietary supplements. During the presystemic biotransformation of flavonoids, mainly sulfate and glucuronide derivatives are produced, which are the dominant metabolites in the circulation. In this study, we tested the interactions of MYR, myricetin-3'-O-sulfate (M3'S), AMP, and ampelopsin-4'-O-sulfate (A4'S) with human serum albumin (HSA), cytochrome P450 enzymes (CYPs), and organic anion-transporting polypeptides (OATPs) using invitro models, including the recently developed method for measuring flavonoid levels in living cells. M3'S and MYR bound to albumin with high affinity, and they showed moderate displacing effects versus the Site I marker warfarin. MYR, M3'S, AMP, and A4'S exerted no or only minor inhibitory effects on CYP2C9, CYP2C19, and CYP3A4 enzymes. M3'S and MYR caused considerable inhibitory actions on OATP1B1 at low micromolar concentrations (IC50 = 1.7 and 6.4 μM, respectively), while even their nanomolar levels resulted in strong inhibitory effects on OATP2B1 (IC50 = 0.3 and 0.4 μM, respectively). In addition, M3'S proved to be a substrate of OATP1B1 and OATP2B1. These results suggest that MYR-containing dietary supplements may affect the OATP-mediated transport of certain drugs, and OATPs are involved in the tissue uptake of M3'S.

Profiling metabolites and exploring metabolism of parabens in human urine using non-target screening and molecular networking

Parabens are widely used as preservatives in food, pharmaceuticals, and cosmetics due to their excellent antimicrobial activities, cost-effectiveness, and stability. Previous studies have demonstrated their harmful potential and ubiquity in the environment and human tissues. This study revealed profiles of parabens and their metabolites in urine samples from a general population of different ages in China using non-target screening. Metabolism of parabens in human bodies was further explored through the identified metabolites in combination of molecular networking. A total of 34 paraben compounds were screened in the urine samples. In addition to 3 identified confidence level 1 (CL1) parent parabens, 3 CL2 compounds were also identified, namely 4-hydroxybenzoic acid, 3,4-dihydroxybenzoic acid, and ethylparaben sulfate. Furthermore, 6 CL3 compounds were tentatively identified, five of which were sulfonated and sulfated metabolites of parabens. The remaining 22 were CL4 features without certain chemical structures. Hazardousness assessment suggested toxic potential of the identified metabolites. Distribution of the parabens and metabolites in the urines showed age-dependent differences. Sulfonation and sulfation were potentially significant metabolic pathways of the parabens in human bodies. This study provides a new insight into understanding metabolism of parabens in human bodies and potential risks of human exposure to parabens.

Characterization of the in vitro penetration and first-pass metabolism of genistein and daidzein using human and pig skin explants and Phenion full-thickness skin models.

OECD test guideline compliant skin penetration studies, which also comply with the SCCS basic criteria, are lacking for genistein and daidzein. Therefore, we have measured their penetration and metabolism using ex vivo explants of fresh (i.e., metabolically viable) pig skin, fresh and frozen human skin, and Phenion full-thickness (FT) models. Preliminary studies using fresh pig skin helped to define the optimal experimental conditions. The dermal absorption of 10nmoles/cm2 genistein and daidzein in ethanol was comparable in all four models. A first-pass metabolism in skin to glucuronide and sulfate metabolites was demonstrated for both chemicals in all models except frozen human skin. The main difference between fresh skin models was the overall extent of metabolism and the relative ratio of each metabolite, for example, much lower sulfate conjugates were formed in pig skin incubations. The extent of parent chemical metabolized and the contribution of the glucuronide pathway were relatively lower in PhenionFT models than in fresh human skin, possibly due to a higher penetration rate in this model and differences in the expression of functional metabolizing enzymes. When metabolism in human skin was abolished by freezing, more radiolabelled chemical remained in the skin tissue but the overall dermal absorption was unchanged. In conclusion, this initial characterization study showed that all models tested indicated that genistein and daidzein extensively penetrated the skin when applied to skin in ethanol. All fresh skin models produced the same metabolites, with the known species difference in the sulfation pathway demonstrated in pig skin.

Effect of vehicle on the in vitro penetration and metabolism of genistein and daidzein in ex vivo skin explants and the Phenion full-thickness skin model.

In a read-across assessment of the safety of genistein and daidzein in cosmetic products, additional information was required to account for differences in their systemic exposure after topical application in a typical body lotion formulation. Therefore, we measured the penetration and metabolism of two doses (3 and 30 nmoles/cm2) of genistein and daidzein applied in ethanol and in a body formulation to fresh pig skin, fresh and frozen human skin, and PhenionFT models. Both chemicals readily penetrated all skin models when applied in ethanol. The same sulfate and glucuronide metabolites were formed in fresh pig skin, fresh human skin, and PhenionFT models, which also all demonstrated that (a) these pathways could be saturated between 3 and 30 nmoles/cm2 and (b) the extent of metabolism of daidzein was lower than genistein. Although the relative amounts of radiolabeled chemical in human skin and medium compartments were altered by freezing, their overall bioavailability was not affected. The greatest impact on the bioavailability and distribution of both chemicals was observed when they were applied in the formulation. Most of the dose applied in the formulation was retained on the skin surface, especially at 30 nmoles/cm2 (60%-90%), resulting in much lower amounts in the medium and/or skin. In conclusion, all four skin models demonstrated first-pass metabolism of genistein and daidzein and a marked alteration in their disposition by applying them in a body lotion formulation. This supports the use of fresh pig skin and PhenionFT models as alternatives to human skin for investigating skin metabolism and formulation effects for these two chemicals. The results were used to develop the dermal module of a PBPK model and dose setting for organ-on-chip experiments. They could also be used to refine internal exposure estimates in regulatory safety assessments.

Mechanistic Insights into the Biological Effects and Antioxidant Activity of Walnut (Juglans regia L.) Ellagitannins: A Systematic Review.

Walnuts (Juglans regia L.) are an important source of ellagitannins. They have been linked to positive effects on many pathologies, including cardiovascular disorders, neurodegenerative syndromes, and cancer. The limited bioavailability of ellagitannins prevents them from reaching significant circulatory levels, despite their antioxidant, anti-inflammatory, and chemopreventive properties. Urolithins are ellagitannin gut microbiota-derived metabolites. They have better intestinal absorption and may be responsible for the biological activities of ellagitannins. Recent evidence showed that walnut ellagitannins and their metabolites, urolithins, could have positive outcomes for human health. This study aims to synthesize the current literature on the antioxidant activity and mechanistic pathways involved in the therapeutic potential of walnut ellagitannins and their metabolites. In the eligible selected studies (n = 31), glansreginin A, pedunculagin, and casuarictin were the most prevalent ellagitannins in walnuts. A total of 15 urolithins, their glucuronides, and sulfate metabolites have been identified in urine, blood, feces, breast milk, and prostate tissue in analyzed samples. Urolithins A and B were associated with antioxidant, anti-inflammatory, cardioprotective, neuroprotective, anticarcinogenic, and anti-aging activities, both in preclinical and clinical studies. Despite the promising results, further well-designed studies are necessary to fully elucidate the mechanisms and confirm the therapeutic potential of these compounds in human health.

COVID-19 vaccine adverse events: Evaluating the pathophysiology with an emphasis on sulfur metabolism and endotheliopathy.

In this narrative review, we assess the pathophysiology of severe adverse events that presented after vaccination with DNA and mRNA vaccines against COVID-19. The focus is on the perspective of an undersulfated and degraded glycocalyx, considering its impact on immunomodulation, inflammatory responses, coagulation and oxidative stress. The paper explores various factors that lead to glutathione and inorganic sulfate depletion and their subsequent effect on glycocalyx sulfation and other metabolites, including hormones. Components of COVID-19 vaccines, such as DNA and mRNA material, spike protein antigen and lipid nanoparticles, are involved in possible cytotoxic effects. The common thread connecting these adverse events is endotheliopathy or glycocalyx degradation, caused by depleted glutathione and inorganic sulfate levels, shear stress from circulating nanoparticles, aggregation and formation of protein coronas; leading to imbalanced immune responses and chronic release of pro-inflammatory cytokines, ultimately resulting in oxidative stress and systemic inflammatory response syndrome. By understanding the underlying pathophysiology of severe adverse events, better treatment options can be explored.

Sulfated vitamin D metabolites represent prominent roles in serum and in breastmilk of lactating women

BackgroundConcentrations of vitamin D (VitD) and 25-hydroxyvitamin D (25OHD) in breastmilk are low despite the essential role of VitD for normal infant bone development, yet additional metabolic forms of vitamin D may be present. This study evaluates the contribution of sulfated vitamin D metabolites, vitamin D3-sulfate (VitD3-S) and 25-hydroxyvitamin D3-sulfate (25OHD3-S) for lactating women and assesses the response to high-dose VitD3 supplementation. MethodsSerum and breastmilk were measured before and after 28 days with 5000 IU/day VitD3 intake in 20 lactating women. Concentrations of VitD3-S and 25OHD3-S in milk, and 25OHD2, 25OHD3, 25OHD3-S, VitD3 and VitD3-S in serum were determined by mass spectrometry. ResultsBaseline vitamin D status was categorized as sufficient (mean ± SD serum 25OHD3 69 ± 19 nmol/L), and both serum VitD3 and 25OHD3 increased following supplementation (p < 0.001). 25OHD3-S was 91 ± 19 nmol/L in serum and 0.47 ± 0.09 nmol/L in breastmilk. VitD3-S concentrations were 2.92 ± 0.70 nmol/L in serum and 6.4 ± 3.9 nmol/L in breastmilk. Neither sulfated metabolite significantly changed with supplementation in either serum or breastmilk. ConclusionsSulfated vitamin D metabolites have prominent roles for women during lactation with 25OHD3-S highly abundant in serum and VitD3-S distinctly abundant in breastmilk. These data support the notion that 25OHD3-S and VitD3-S may have physiological relevance during lactation and nutritional usage for nursing infants.

Wastewater-based epidemiology methodology to investigate human exposure to bisphenol A, bisphenol F and bisphenol S.

Wastewater-based epidemiology (WBE) has become an invaluable tool for tracking the evolution of use or exposure of/to numerous substances. Bisphenols, commonly utilized in manufacturing plastic goods, have been categorized as endocrine disrupting chemicals, underscoring the critical need for real-time data on their local-level exposure to safeguard public health. In this study, we have developed a novel analytical method and WBE framework for the assessment of population-level exposure to bisphenol A (BPA) and its most prominent substitutes, bisphenols F and S (BPF and BPS), through the determination their Phase II metabolites in wastewater by WBE. Stability and exclusivity tests denoted that glucuronides are not stable in sewage, whereas sulfate metabolites are good biomarkers. Therefore, a solid-phase extraction followed by liquid chromatography-tandem mass spectrometry method was developed for the bisphenols’ monosulfates and BPA bissulfate. The analytical method was validated with three different wastewater matrices, providing trueness (as recovery) in the 79–112 % range with relative standard deviations < 12 %, and method quantification limits below 2 ng L−1 for monosulfates, but higher (35 ng L−1) for BPA bissulfate. Subsequently, the method was applied to 24h-composite raw wastewater samples collected over a week in 4 different locations in Spain and Portugal. BPA bissulfate was not detected, but the three monosulfate metabolites of each bisphenol were positively detected in the samples, being the metabolite of BPA the most prevalent, followed by those of BPF and BPS. Community-wide BPA intake was then estimated to be higher than the European Food Safety Agency (EFSA) tolerable daily intake (TDI) of 2 × 10−4 µg kg−1day−1 in all locations. In the case of BPF and BPS, there is not enough metabolism data or even established limit, but they would also surpass safe levels in several locations if a similar metabolism and TDI would be assumed. This innovative method could be used to a larger set of wastewater-treatment plants as an early-warning approach on human exposure to bisphenols.

Regulatory effects of antioxidants on indoxyl sulfate-enhanced intracellular oxidation and impaired phagocytic activity in differentiated U937 human macrophage cells.

Indoxyl sulfate (IS), a uremic toxin, is a physiologically active sulfated metabolite, specifically in kidney failure patients. Our previous studies have shown that IS downregulates phagocytic immune function in a differentiated HL-60 human macrophage cell model. However, it remains unclear whether IS exerts similar effects on macrophage function in other cell types or in lipopolysaccharide (LPS)-sensitive immune cell models. Therefore, this study aimed to investigate the effects of IS on intracellular oxidation levels and phagocytic activity in a differentiated U937 human macrophage cell model, both in the absence and presence of LPS. Our results demonstrated that IS significantly increases intracellular oxidation levels and decreases phagocytic activity, particularly in cells activated by LPS. Furthermore, we found that 2-acetylphenothiazine, an NADH oxidase inhibitor, attenuates the effects of IS in LPS-activated macrophage cells. Representative antioxidants, trolox, α-tocopherol, and ascorbic acid, significantly mitigated the effects of IS on the macrophages responding to LPS.

A multi-technique based analytical platform for characterization and identification of a newly emerged steroid 6β-chlorotestosterone and its in-vivo epimeric metabolites

Doping athletes tend to use new and non-approved drugs in an attempt to circumvent the dope test. Recently, a package of unknown drug was obtained from black market claiming to contain steroid-like compound, which could not be readily identified due to the lack of commercially available reference standards. In order to characterize and identify the chemical structure of the unknown compound, ultra performance liquid chromatography high resolution mass spectrometry (UPLC-HRMS), high performance liquid chromatography tandem quadrupole mass spectrometry (HPLC-MS/MS), gas chromatography tandem quadrupole mass spectrometry (GC–MS/MS) and nuclear magnetic resonance (NMR) instruments were applied in this work. Based on the combined data, the unknown compound was identified as 6β-chlorotestosterone. The aim of this study was to find urinary metabolic biomarkers of 6β-chlorotestosterone for clinical research and doping control analysis. Ten in-vivo metabolites including four phase I metabolites and six phase II metabolites were characterized and potentially identified. The detailed structure of the phase I metabolite was successfully obtained by GC–MS/MS analysis of trimethylsilylation (TMS) released upon dissolution, overcoming the absence of useful fragment ions to demonstrate the structure of sulfate metabolites. Two strategies including metabolic mechanisms and retention time variation of steroids were introduced to determine and distinguish 3α/β- and 5α/β- epimeric metabolites. A comprehensive evaluation was conducted on time of appearance and detection of each metabolite. The sulfate metabolite 6β-chloro-5β-androstan-17-one-3β-O-sulfate (S1) could be detected up to 12 days after oral administration, which was considered to be the long term biomarker for 6β-chlorotestosterone abuse in clinical research and doping control analysis.

Comparative profiling of serum, urine, and feces bile acids in humans, rats, and mice.

Bile acids (BAs) play important pathophysiological roles in both humans and mammalian animals. Laboratory rats and mice are widely used animal models for assessing pharmacological effects and their underlying molecular mechanisms. However, substantial physiological differences exist in BA composition between humans and murine rodents. Here, we comprehensively compare BA profiles, including primary and secondary BAs, along with their amino acid conjugates, and sulfated metabolites in serum, urine, and feces between humans and two murine rodents. We further analyze the capabilities in gut microbial transform BAs among three species and compare sex-dependent variations within each species. As a result, BAs undergo amidation predominately with glycine in humans and taurine in mice but are primarily unamidated in rats. BA sulfation is a unique characteristic in humans, whereas rats and mice primarily perform multiple hydroxylations during BA synthesis and metabolism. For gut microbial transformed BA capabilities, humans are comparable to those of rats, stronger than those of mice in deconjugation and 7α-dehydroxylation, while humans are weak than those of rats or mice in oxidation and epimerization. Such differences enhance our understanding of the divergent experimental outcomes observed in humans and murine rodents, necessitating caution when translating findings from these rodent species to humans.

Chemical Profile and Healthy Properties of Sicilian Diplotaxis harra subsp. crassifolia (Raf.) Maire.

This study was aimed at investigating the phytochemical profile and bioactivity of Diplotaxis harra subsp. crassifolia (Brassicaceae), a species from central-southern Sicily (Italy), where it is consumed as a salad. For this purpose, LC-ESI/HRMSn analysis of the ethanolic extract was performed, highlighting the occurrence, along with flavonoids, hydroxycinnamic acid derivatives, and oxylipins, of sulfated secondary metabolites, including glucosinolates and various sulfooxy derivatives (e.g., C13 nor-isoprenoids, hydroxyphenyl, and hydroxybenzoic acid derivatives), most of which were never reported before in the Brassicaeae family or in the Diplotaxis genus. Following ethnomedicinal information regarding this species used for the treatment of various pathologies such as diabetes and hypercholesterolemia, D. harra ethanolic extract was evaluated for its antioxidant potential using different in vitro tests such as 2,2-diphenyl-1-picrylhydrazyl, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid), Ferric Reducing Ability Power, and β-carotene bleaching tests. The inhibitory activity of carbohydrate-hydrolyzing enzymes (α-amylase and α-glucosidase) and pancreatic lipase was also assessed. In the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid assay, an IC50 value comparable to the positive control ascorbic acid (2.87 vs. 1.70 μg/mL, respectively) was obtained. The wild-wall rocket salad extract showed a significant α-amylase inhibitory effect. Obtained results indicate that Sicilian wild-wall rocket contains phytochemicals that can prevent hyperglycemia, hyperlipidemia, and obesity.

Differences in Metabolite Profiles of Dihydroberberine and Micellar Berberine in Caco-2 Cells and Humans-A Pilot Study.

We investigated the pharmacokinetic pathway of berberine and its metabolites in vitro, in Caco-2 cells, and in human participants following the administration of dihydroberberine (DHB) and micellar berberine (LipoMicel®, LMB) formulations. A pilot trial involving nine healthy volunteers was conducted over a 24 h period; blood samples were collected and subjected to Ultra High-Performance Liquid Chromatography-High Resolution Mass Spectrometry (UHPLC-HRMS) analyses to quantify the concentrations of berberine and its metabolites. Pharmacokinetic correlations indicated that berberrubine and thalifendine follow distinct metabolic pathways. Additionally, jatrorrhizine sulfate appeared to undergo metabolism differently compared to the other sulfated metabolites. Moreover, berberrubine glucuronide likely has a unique metabolic pathway distinct from other glucuronides. The human trial revealed significantly higher blood concentrations of berberine metabolites in participants of the DHB treatment group compared to the LMB treatment group-except for berberrubine glucuronide, which was only detected in the LMB treatment group. Similarly, results from in vitro investigations showed significant differences in berberine metabolite profiles between DHB and LMB. Dihydroberberine, dihydroxy-berberrubine/thalifendine and jatrorrhizine sulfate were detected in LMB-treated cells, but not in DHB-treated cells; thalifendine and jatrorrhizine-glucuronide were detected in DHB-treated cells only. While DHB treatment provided higher blood concentrations of berberine and most berberine metabolites, both in vitro (Caco-2 cells) and in vivo human studies showed that treatment with LMB resulted in a higher proportion of unmetabolized berberine compared to DHB. These findings suggest potential clinical implications that merit further investigation in future large-scale trials.

A water-soluble preparation for intravenous administration of isorhamnetin and its pharmacokinetics in rats

Flavonoids are considered as health-protecting food constituents. The testing of their biological effects is however hampered by their low oral absorption and complex metabolism. In order to investigate the direct effect(s) of unmetabolized flavonoid, a preparation in a biologically friendly solvent for intravenous administration is needed. Isorhamnetin, a natural flavonoid and a human metabolite of the most frequently tested flavonoid quercetin, has very low water solubility (<3.5 μg/mL). The aim of this study was to improve its solubility to enable intravenous administration and to test its pharmacokinetics in an animal model. By using polyvinylpyrrolidone (PVP10) and benzalkonium chloride, we were able to improve the solubility approximately 600 times to 2.1 mg/mL. This solution was then administered intravenously at a dose of 0.5 mg/kg of isorhamnetin to rats and its pharmacokinetics was analyzed. The pharmacokinetics of isorhamnetin corresponded to two compartmental model with a rapid initial distribution phase (t1/2α: 5.7 ± 4.3 min) and a slower elimination phase (t1/2β: 61 ± 47.5 min). Two sulfate metabolites were also identified. PVP10 and benzalkonium did not modify the properties of isorhamnetin (iron chelation and reduction, and cell penetration) substantially. In conclusion, the novel preparation reported in this study is suitable for future testing of isorhamnetin effects under in vivo conditions.

Characterization and quantitation of a sulfoconjugated metabolite for detection of methyltestosterone misuse and direct identification by LC-MS

Methyltestosterone (MT) is one of the most frequently misused anabolic androgenic steroids detected in doping control analysis. The metabolism of MT in humans leads to several phase І metabolites and their corresponding phase Ⅱ conjugates. Previous studies have postulated the 3α-sulfoconjugate of 17α-methyl-5β-androstane-3α,17β-diol (S2) as principal sulfate metabolite of MT, with a detection window exceeding 10 days. However, a final direct and unambiguous confirmation of the structure of this metabolite is missing until now. In this study, we established an approach to detect and identify S2, using intact analysis by liquid chromatography hyphenated with tandem mass spectrometry (LC-MS/MS) without complex sample pretreatment. An in vitro study yielded the LC-MS/MS reference retention times of all 3-sulfated 17-methylandrostane-3,17-diol diastereomers, allowing for accurate structure assignment of potentially detected metabolites. In an in vivo excretion study with a single healthy male volunteer, the presence of the metabolite S2 was confirmed after a single oral dose of 10 mg MT. The reference standard was chemically synthesized, characterized by accurate mass mass spectrometry (MS) and nuclear magnetic resonance (NMR), and quantified by quantitative NMR (qNMR). Thus, this study finally provides accurate structure information on the S2 metabolite and a direct analytical method for detection of MT misuse. The availability of the reference material is expected to facilitate further evaluation and subsequent analytical method validation in anti-doping research.

Thermodynamics analysis of acetaminophen and its metabolites using density functional theory

AbstractThe thermodynamics factors of acetaminophen and its metabolites were considered using density functional theory (DFT) at 298.15 K temperature and 1 atm. pressure. The resultant Thermodynamics factors were at that time analyzed and compared to determine the influence of temperature and pressure on the stability of the metabolite and its potential behavior in changed environments. The results display that the internal energy, enthalpy, Gibbs free energy, entropy, heat capacity at constant volume (Cv), and Cp at constant pressure (Cp) all affected by the temperature increases. The internal energy (U) of the most stable molecule increases with the increase in temperature, while the heat capacity (H) decreases with the decrease in pressure. The heat capacity and heat capacity of sulfate (APS) are stable at changed temperatures and pressures. These results will make available valued information on the Thermodynamics behavior of Acetaminophen (AP), Acetaminophen cysteine (APCys), Acetaminophen glucuronide (APGlc), and Acetaminophen sulfate (APS) metabolites which can be used to recognize their behavior in the body and how they are metabolized. Furthermore, the results of this study will be responsible for a better understanding of the thermal stability of these molecules under different conditions and guide the development of new drugs and therapies.

Metabolomic profiles of sleep-disordered breathing are associated with hypertension and diabetes mellitus development

Sleep-disordered breathing (SDB) is a prevalent disorder characterized by recurrent episodic upper airway obstruction. Using data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), we apply principal component analysis (PCA) to seven SDB-related measures. We estimate the associations of the top two SDB PCs with serum levels of 617 metabolites, in both single-metabolite analysis, and a joint penalized regression analysis. The discovery analysis includes 3299 individuals, with validation in a separate dataset of 1522 individuals. Five metabolite associations with SDB PCs are discovered and replicated. SDB PC1, characterized by frequent respiratory events common in older and male adults, is associated with pregnanolone and progesterone-related sulfated metabolites. SDB PC2, characterized by short respiratory event length and self-reported restless sleep, enriched in young adults, is associated with sphingomyelins. Metabolite risk scores (MRSs), representing metabolite signatures associated with the two SDB PCs, are associated with 6-year incident hypertension and diabetes. These MRSs have the potential to serve as biomarkers for SDB, guiding risk stratification and treatment decisions.

Host-microbiome orchestration of the sulfated metabolome.

Recent studies have demonstrated that metabolites produced by commensal bacteria causally influence health and disease. The sulfated metabolome is one class of molecules that has recently come to the forefront due to efforts to understand the role of these metabolites in host-microbiome interactions. Sulfated compounds have canonically been classified as waste products; however, studies have revealed a variety of physiological roles for these metabolites, including effects on host metabolism, immune response and neurological function. Moreover, recent research has revealed that commensal bacteria either chemically modify or synthesize a variety of sulfated compounds. In this Review, we explore how host-microbiome collaborative metabolism transforms the sulfated metabolome. We describe bacterial and mammalian enzymes that sulfonate and desulfate biologically relevant carbohydrates, amino acid derivatives and cholesterol-derived metabolites. We then discuss outstanding questions and future directions in the field, including potential roles of sulfated metabolites in disease detection, prevention and treatment. We hope that this Review inspires future research into sulfated compounds and their effects on physiology.

Pharmacokinetics of Hydroxytyrosol and Its Sulfate and Glucuronide Metabolites after the Oral Administration of Table Olives to Sprague-Dawley Rats.

The pharmacokinetics (PK) of hydroxytyrosol and its metabolites were characterized following oral administration to Sprague-Dawley rats of 3.85 and 7.70 g of destoned Arbequina table olives/kg. Plasma samples were analyzed using a fully validated method consisting of liquid extraction followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Noncompartmental PK analysis of hydroxytyrosol demonstrated linear PK between doses of 2.95 and 5.85 mg hydroxytyrosol/kg. Half-life was approximately 2.5 h, while mean residence time was around 4 h. Clearance occurred by conversion to two sulfate and two glucuronide conjugates. The area under the plasma concentration-time curve (AUC) ratios of metabolites versus parent hydroxytyrosol was approximately 7-9-fold for the sulfate and below 0.25 for the glucuronide, indicating sulfation as the predominant metabolic pathway. Despite extensive metabolism, hydroxytyrosol remained in plasma for up to 8 h with AUCs of 4293 and 8919 min·nmol/L for the doses of 3.85 and 7.70 g/kg, respectively. Therefore, table olives provide a more sustained plasma profile than other foods containing hydroxytyrosol, which may enhance its health-protecting activities.