Fecal Excretion Rates Research Articles

A physiologically based toxicokinetic model for microplastics and nanoplastics in mice after oral exposure and its implications for human dietary exposure assessment

Evidence of microplastics (MPs) and nanoplastics (NPs) in foods and daily-use products, along with their frequent detection in the human body, has raised concerns regarding their potential impact on human health through dietary ingestion. However, there is a lack of quantitative tools to simulate their bioaccumulation and tissue distribution following environmental exposure. To address this gap, we developed the first physiologically based toxicokinetic (PBTK) model for predicting the biodistribution of MPs and NPs in mice following oral exposure under various exposure scenarios. This novel model incorporated key kinetic mass transport processes, such as membrane permeability, albumin binding, and cellular uptake. We identified that the absorption rate in the gastrointestinal tract and fecal excretion rate constant had significant impacts on organ dosimetry. Our regression analysis indicated that the size-dependent dissociation constant and urine clearance rate constant sharply increased by a factor of 3 as NPs particle size increased to 1µm. Finally, we developed a graphical user interface to enable interactive visualization and analysis for future applications, supporting human dietary exposure and risk assessment using available food consumption data and MPs/NPs residue data. The simulation results offer a mechanistic perspective, enhancing understanding of the internal organ dosimetry burden and health impacts from dietary exposure to MPs and NPs.

Urinary and Fecal Excretion of 121 Environmental Chemicals in Pet Dogs and Cats: Significance of Feces in Biomonitoring of Exposures.

Laboratory animal studies have reported the biliary excretion of chemicals following exposure. Nevertheless, feces are rarely used as a matrix in biomonitoring of chemical exposures. In this study, feces and urine from pet dogs and cats were analyzed for the presence of 45 plasticizers, 45 environmental phenols, and 31 pesticides. Thirty-two analytes were detected in ≥70% pet feces, while up to 29 analytes were frequently (≥70%) found in urine. The sum concentrations of all analytes (∑All) in pet feces were significantly higher than those measured in urine (median: 393-666 ng/g wet weight in feces vs 216-464 ng/mL in urine). Plasticizers were the dominant class of chemicals, accounting for 81-97% and 69-77% of ∑All in urine and feces, respectively. Analyte concentrations measured in paired urine and feces exhibited weak correlations. The excretion rates of the chemicals via urine and feces were calculated through a reverse dosimetry approach. Low-molecular-weight phthalates excreted predominantly in urine, whereas high-molecular-weight phthalates and several organophosphate triesters were excreted predominantly in feces. The fecal excretion rates of parabens, benzophenones, bisphenols, naphthalene, 2,4-dichloronicotinic acid, and 4-nitrophenol were similar to or higher than those of urinary excretion. Our results suggest that feces are an important matrix in biomonitoring of exposure to environmental chemicals.

Analysis of current equine feeding practices in the Netherlands and identification of potential nutrient leaching and environmental contamination factors

The aim of this study was to estimate the potential for nutrient leaching based on current feeding practices of horses in the Netherlands. An online survey of horse owners collected data on the demographics of the horses (n = 274) and feeding practices. The median age was 8 years, the majority being warmblood and geldings with a mean bodyweight of 542.4 ± 101.9 kg. Most horses (85 %) had access to a limited area of pasture (<200m2 per horse), with a median grazing time of 10 hours. Grass hay was the predominant conserved forage offered (77 %) within diets. Concentrate feeds were provided to most horses (93.8 %) as well as the dietary supplements (80 %). The majority of the horses were offered high levels of metabolizable energy (ME) (90 %), starch (mean 2.4 ± 0.8 g/kg bw) and sugar intake (mean 1.4 ± 1.2 g/kg bw) compared to NRC recommendations. The estimated potential nitrogen excretion per horse per day was 228 ± 134 g, or 8.47 kg of nitrogen per ton of manure. Consequently, the estimated daily fecal excretion rates of microminerals for each horse were as follows: Copper (Cu) at 141.0 ± 151.3 mg, Zinc (Zn) at 593.1 ± 504.4 mg, Manganese (Mn) at 957 ± 541.2 mg, and Cobalt (Co) at 2.3 ± 3.5 mg. The analysis indicated that many equine diets in the Netherlands offered excess ME, CP and the minerals Cu, Zn, Mn and Co. To mitigate these concerns, it is crucial to promote sustainable feeding practices and better educate horse owners.

Toxicokinetics of rare earth element oxides administered intravenously to rats

Rare earth elements (REEs) are increasingly used in a wide range of applications. However, their toxicokinetic behaviors in animals and humans are not yet fully documented, hindering health risk assessments. We used a rat experimental model to provide novel data on the toxicokinetics of the insoluble oxide forms of praseodymium (Pr), neodymium (Nd), cerium (Ce) and yttrium (Y) administered intravenously. Detailed blood, urinary and fecal time courses were documented through serial sampling over 21 days in male Sprague-Dawley rats exposed to a mixture of these REE oxides administered at two different doses (0.3 or 1 mg kg−1 bw of each REE oxide commercially sold as bulk μm-sized particles). Tissue REE levels at the time of sacrifice were also measured. Significant effects of the dose on REE time courses in blood and on cumulative urinary and fecal excretion rates were observed for all four REE oxides assessed, as lower cumulative excretion rates were noted at the higher REE dose. In the liver, the main accumulation organ, the fraction of the administered REE dose remaining in the tissue at necropsy was similar at both doses. Toxicokinetic data for the REE oxides were compared to similar data for their chloride salts (also administered intravenously in a mixture, at 0.3 and 1 mg kg−1 bw of each REE chloride) obtained from a previous study. Compared to their chloride counterparts, faster elimination of REE oxides from the blood was observed in the first hours post-dosing. Furthermore, higher mean residence time (MRT) values as well as slower cumulative urinary and fecal excretion were determined for the REE oxides. Also, while liver REE retention was similar for both REE forms, the fractions of the administered REEs recovered in the spleen and lungs were noticeably higher for the REE oxides, at both dose levels. This study highlights the importance of both the dose and form of the administered REEs on their toxicokinetic profiles. Results indicate that chronic exposure and increased doses of REEs may favor bioaccumulation in the body, in particular for insoluble oxide forms of REEs, which are eliminated more slowly from the body.

Distribution and Elimination of Deltamethrin Toxicity in Laying Hens.

Deltamethrin, an important pyrethroid insecticide, is frequently detected in human samples. This study aims to assess the potential effects of deltamethrin on human health and investigate the patterns of residue enrichment and elimination in 112 healthy laying hens. These hens were administered 20 mg·kg-1 deltamethrin based on their body weight. Gas chromatography-mass spectrometry (GC-MS) was used to investigate the residue enrichment pattern and elimination pattern of deltamethrin in the hens. The results indicated a significant increase in the concentration of deltamethrin in chicken manure during the treatment period. By the 14th day of administration, the concentration of deltamethrin in the stool reached 13,510.9 ± 172.24 μg·kg-1, with a fecal excretion rate of 67.56%. The pulmonary deltamethrin concentration was the second highest at 3844.98 ± 297.14 μg·kg-1. These findings suggest that chicken feces contain substantial amounts of deltamethrin after 14 days of continuous administration, and that it can easily transfer to the lungs. After 21 days of drug withdrawal, the residual concentration of deltamethrin in the fat of laying hens was 904.25 ± 295.32 μg·kg-1, with a half-life of 17 days and a slow elimination rate. In contrast, the lungs showed relatively low elimination half-lives of 0.2083 days, indicating faster elimination of deltamethrin in this tissue. These results highlight differences in the rate of deltamethrin elimination in different tissues during drug withdrawal. The fat of laying hens exhibited the highest residue of deltamethrin and the slowest elimination rate, while the lungs showed the fastest elimination rate. Moreover, deltamethrin was found to accumulate in the edible tissues of eggs and laying hens, suggesting that humans may be exposed to deltamethrin through food.

Phytochemical screening, in vitro and in vivo effects of an aqueous extract of the bark of Combretum glutinosum Perr ex DC. (Combretaceae) on gastrointestinal strongyles

IntroductionPlants remain an inexhaustible source of medicines for the treatment of various diseases. The aim of this study was to evaluate the anthelmintic activity of the aqueous extract of Combretum glutinosum bark on adult gastrointestinal strongyle worms. MethodsIn vitro, the extract was contacted with worms at various doses. In vivo, 25 sheep were divided into five batches of 5 animals, with one batch untreated, one batch treated with albendazole and three batches treated with the extract at three different doses. The body weight of the animals, the number of eggs per gram of faeces and haematological parameters were used to assess the efficacy of the extract. ResultsIn vitro, the extract appeared to inhibit the motility of adult Haemonchus contortus worms more than Trichostrongylus colubriformis (P < 0.05). In vivo, a significant reduction in the faecal excretion rate was observed in batches of animals treated with the drug and those treated with the extract, compared with the untreated control. Similarly, an increase in animal weight and an improvement in haematological parameters were observed in the treated batches after experimentation. The chemical profile of the extract revealed the presence of various chemical groups suspected of being responsible for its anthelmintic properties. ConclusionTreatment at a dose of 100 mg/kg body weight appeared to be more active in reducing the number of eggs per gram of faeces and could therefore be recommended for the formulation of an improved traditional medicines with anthelmintic properties.

Development and validation of LC-MS/MS methods for the quantification of 101BHG-D01, a novel, long-acting and selective muscarinic receptor antagonist, and its main metabolite M6 in human plasma, urine and feces: Application to a clinical study in healthy Chinese subjects

101BHG-D01 is a novel, long-acting and selective muscarinic receptor antagonist for the treatment of chronic obstructive pulmonary disease (COPD) and rhinorrhea in rhinitis. To support its clinical study, several liquid chromatography tandem mass spectrometry (LC-MS/MS) methods for the quantification of 101BHG-D01 and its main metabolite M6 in human plasma, urine and feces were developed. The plasma samples were prepared by protein precipitation, and the urine and fecal homogenate samples were pretreated by direct dilution, respectively. The chromatographic separation was performed on an Agilent InfinityLab Poroshell 120 C18 column with 0.1% formic acid and 10.0 mM ammonium acetate buffer solution in water and methanol as the mobile phase. The MS/MS analysis was performed by using multiple reaction monitoring (MRM) under a positive ion electrospray ionization mode. The methods were validated with regards to selectivity, linearity, lower limit of quantitation (LLOQ), accuracy and precision, matrix effect, extraction recovery, dilution integrity, batch size, carryover and stability. The calibration ranges were as follows: 1.00–800 pg/mL for 101BHG-D01 and 1.00–20.0 pg/mL for M6 in plasma; 0.0500–20.0 ng/mL for 101BHG-D01 and M6 in urine; 0.400–400 ng/mL for 101BHG-D01 and 0.100–100 ng/mL for M6 in feces. There was no endogenous or cross interference observed at the retention time of the analytes and internal standard in various biological matrices. Across these matrices, for the lower limit of quantitation quality control (LLOQ QC) samples, the intra- and inter-batch coefficients of variation were within 15.7%. For other QC samples, the intra- and inter-batch coefficients of variation were within 8.9%. The intra- and inter-batch accuracy deviations for all QC samples were within the range of − 6.2–12.0%. No significant matrix effect was observed from the matrices. The extraction recoveries of these methods at different concentrations were consistent and reproducible. The analytes were stable in different matrices under various storage conditions. The other bioanalytical parameters were also fully validated and met the criteria given in the FDA guidance. These methods were successfully applied to a clinical study in healthy Chinese subjects after a single dose administration of 101BHG-D01 inhalation aerosol. After inhalation, 101BHG-D01 was absorbed into plasma rapidly with the time to reach the maximum drug concentration (Tmax) of 5 min and eliminated slowly with a half-life time about 30 h. The cumulative urinary and fecal excretion rates revealed 101BHG-D01 was mainly excreted in feces, rather than urine. The pharmacokinetic results of the study drug laid a foundation for its further clinical development.

Study of the effects of butyric acid and propanediol of the intestine in ICR mice

The effect of gut microbiota correctors on the motility of the gastrointestinal tract of ICR mice was studied. Two feed additives were used - compositions based on glycerol and 1.3 propanediol and Salkoli Mono BP Dry. Three groups of 10-12 animals each were formed according to the principle of analogues: two experimental and one control. Experimental feed mixtures were made by saturating 200 g of feed with sunflower oil, 1.3 propanediol, glycerol (experimental group 1); the feed mixture of experimental group 2 was additionally mixed with the feed additive Salkoli Mono BP Dry. To estimate the rate of fecal excretion, 100 µl of fluorescent tags (fluorescent ink green and red) were given to mice of all groups, previously mixed with water 1: 1. The timing of the appearance of the first signs of fluorescence in feces in animals of the control and experimental groups was estimated. Intensive fluorescence of the green label in fluorimetry samples was observed. The greatest increase in fluorescence was observed at the 4th hour of the experiment in the control group, while in the 2nd experimental group the increase lasted until the 5th hour. In the 1st experimental group, elimination of the main amount of green dye did not begin even by the 5th hour of the experiment. The method using fluorescent tags revealed a delay in mixing of feed masses in mice fed glycerol and 1,3 propanediol, which was accompanied by a statistically significant increase in Escherichia coli concentration - by 3 times (p &lt; 0.05). The use of Salkoli Mono BP Dry had no statistically significant effect on E. coli concentrations and gastrointestinal motility.

A Prussian blue analog as a decorporation agent for the simultaneous removal of cesium and reactive oxygen species.

Radioactive cesium (Cs) is a significant concern due to its role as a major byproduct of nuclear fission and its potential for radioactive contamination. Internal contamination with radioactive Cs is characterized by immoderate production of reactive oxygen species (ROS), resulting in severe radiation damage. Therefore, the development of therapeutic strategies should focus on enhancing the excretion of radioactive Cs and reducing radiation-induced oxidative damage. However, current therapeutic drugs like Prussian blue (PB) have limited efficacy in addressing these issues. In this study, we present Cu3[Fe(CN)6]2 (CuFe) nanoparticles, a Prussian blue analog (PBA), which can not only efficiently sequester Cs but also exhibit resistance against radiation damage. The results of the adsorption studies demonstrate that CuFe outperforms PB in terms of adsorption performance. Further mechanistic investigations indicate that the increased adsorption capacity of CuFe may be attributed to the presence of additional defects resulting from the [Fe(CN)6] missing linkers. Moreover, CuFe mimics the functions of catalase (CAT) and superoxide dismutase (SOD) by effectively eliminating O2˙- and H2O2 while scavenging ˙OH, thereby mitigating ROS induced by radiative Cs. Importantly, in vivo study confirms the efficient Cs decorporation capability of CuFe. The fecal cumulative excretion rate of CuFe reaches 69.5%, which is 1.45 times higher than that of PB (48.8%). These findings demonstrate that CuFe exhibits excellent Cs removal performance and ROS scavenging ability, making it an attractive candidate for the treatment of Cs contamination.

Pharmacokinetic evaluation and relative bioavailability pilot study of fidaxomicin in healthy Chinese subjects: An open, randomized, single-dose, cross-over study.

To compare the pharmacokinetic (PK) characteristics, investigate relative bioavailability, and provide data for potential additional bioequivalence trials between generic fidaxomicin (test (T) formulation) and the original brand (reference (R) formulation) in healthy Chinese subjects. An open, randomized, single-dose, cross-over study was conducted in 18 healthy Chinese subjects. The subjects randomly received T or R formulations and the alternative formulations were received after a 14-day wash-out period. Blood and fecal samples were collected and tested by liquid chromatography-tandem mass spectrometry (LC-MS/MS). PK parameters were calculated using a non-compartmental model. Relative bioavailability considering commonly established bioequivalence criteria was assessed. Cmax were 3.58±2.74 ng/mL and 6.01±3.93 ng/mL, and AUC0-∞ were 35.71±18.68 h×ng/mL and 52.15±31.31 h×ng/mL for the T and R formulations, respectively. The tmax of both formulations was 5.00hours. The cumulative fecal excretion rate (Fe0-96h/F) of fidaxomicin and its main active metabolite OP-1118 were similar for both formulations. The geometric mean ratios and 90% confidence intervals (CI) of AUC0-t, AUC0-∞, and Cmax were not completely within the range of 80.00-125.00%. Significant within-subject and inter-subject coefficients of variation (> 30%) were found. Despite the differences in exposure, PK characteristics and fecal recovery of the two formulations were similar, suggesting that an effective concentration of the generic fidaxomicin could be achieved locally in the gastrointestinal tract. Fidaxomicin was a highly viable drug, thus providing reference for future clinical study design.

Refining wastewater-based epidemiology for cannabis consumption monitoring: Relevance of analysing both the aqueous phase and suspended solids of influent wastewater

Evaluating the relevance of analyzing the aqueous phase and the suspended solids of influent wastewater (IWW) samples in the frame of monitoring cannabis consumption trends. Wastewater-based epidemiology (WBE) employs the analysis of human metabolic excretion products of xenobiotics in IWW with the aim of estimating their community use. Since cannabis is the most frequently used illicit drug, it is imperative to have accurate analytical methods available to measure cannabis biomarker Δ9-tetrahydrocannabinol (THC) and its major metabolites THC-OH and THC-COOH in IWW. Solid-phase extraction (SPE) is most commonly used as sample preparation method to isolate the biomarkers from the liquid phase of IWW. However, the analysis of the suspended solids and the application of the excretion rates in faeces are mostly ignored. To improve the estimation of cannabis consumption through WBE, both the aqueous phase and the suspended solids of IWW should be considered. In this study, liquid-liquid extraction (LLE) has been applied to obtain concentrations of the major biomarkers of cannabis (THC, THC-OH and THC-COOH) of the sorbed and dissolved phases of IWW. Using LLE, no filtration or centrifugation step is required prior to extraction in contrast with SPE and, therefore, the analytes present in suspended solids could be also simultaneously measured. LLE was applied to various IWW samples to extract both the full raw sample and the liquid phase obtained after centrifugation. In addition, extraction with a mixture of hexane-ethyl acetate was applied to the suspended solids separated from centrifugation of IWW. No significant differences were found when SPE or LLE were applied to the extraction of the liquid phase only, as both led to acceptable recoveries, 90% and 75% respectively. Therefore, both techniques could be used for the determination of cannabis biomarkers in the centrifuged liquid phase of IWW. After centrifugation of the samples, the separate analysis of the liquid phase and suspended solids in the IWW samples revealed that a significant fraction of the three biomarkers was present in the suspended solids (86% THC, 62% THC-OH, and 44% THC-COOH). In addition, the total amount of cannabis biomarkers observed by analyzing raw IWW on the one hand, and by separate analysis of the liquid phase and the suspended solids on the other hand, was in good agreement. Since SPE requires a centrifugation step, a significant amount of cannabis biomarkers present in the suspended solids is not measured. If SPE is used, a correction factor is needed to account for the significant sorption, but further research is required. Based on this new data; the added value, advantages and disadvantages of SPE in comparison with LLE should be reconsidered In WBE to estimate cannabis use, analysis of the suspended solids cannot be ignored. The sole analysis of the liquid phase by applying SPE would lead to a notable underestimation in cannabis biomarker concentration in raw IWW. Therefore, the analysis of the raw IWW by LLE offers more realistic information on the biomarker concentration in IWW leading to more reliable monitoring of cannabis consumption trends. Hence, the complexity of measuring cannabis biomarkers in IWW is better reflected. The preliminary results allowed to identify points to be addressed in future research to improve WBE back-calculations: i) sampling uncertainty related to solids, ii) partition of the cannabis biomarkers between liquid and solid phases, and iii) more accurate urinary and faecal excretion rates to use in consumption calculations.

Urinary and fecal excretion of aromatic amines in pet dogs and cats from the United States

Several primary aromatic amines (AAs) are known or suspected carcinogens. Despite this, the exposure of pet animals to this class of chemicals is unknown. In this study, we investigated the occurrence of 30 AAs and two tobacco chemical markers (nicotine and cotinine) in 63 pet urine (42 dog and 21 cat) and 77 pet feces (37 dog and 40 cat) samples collected from the Albany area of New York State. Eight of the 30 AAs (∑8AAs) were found in > 38% of dog and cat urine samples, at median concentrations of 7.99 (range: 0.42–52.3 ng/mL) and 31.4 (2.63–75.9) ng/mL, respectively. Nine of the 30 AAs (∑9AAs) were found in > 73% of dog and cat feces samples, at median concentrations of 278 (range: 61.7–613 ng/g) and 240 (55.4–645) ng/g dry wt, respectively. Among the 30 AAs, 2,6-dimethylaniline (2,6-DMA) accounted for the highest median concentrations in both urine and fecal samples. Median concentrations of nicotine and cotinine were below 0.92 ng/mL in urine and below 3.86 ng/g in feces of both dogs and cats. No significant relationship was found between AA concentrations and pet age or gender. The lack of significant Spearman’s rank correlation between the concentrations of AA and nicotine in pet urine/feces suggested that sources other than tobacco smoke contributed to AA exposure in pets. Furthermore, the calculated fecal excretion rates of AAs were higher than the intake rates (estimated through reverse dosimetry), which indicates that cats and dogs are exposed to AA precursors such as azo dyes. Concentrations in urine and feces reflected exposure to direct and indirect exposure sources, respectively, of AAs.

NPC1L1 Deficiency Suppresses Ileal Fibroblast Growth Factor 15 Expression and Increases Bile Acid Pool Size in High-Fat-Diet-Fed Mice.

Niemann–Pick C1-like 1 (NPC1L1) mediates intestinal uptake of dietary and biliary cholesterol and is the target of ezetimibe, a cholesterol absorption inhibitor used to treat hypercholesterolemia. Genetic deletion of NPC1L1 or ezetimibe treatment protects mice from high-fat diet (HFD)-induced obesity; however, the molecular mechanisms responsible for this therapeutic benefit remain unknown. A major metabolic fate of cholesterol is its conversion to bile acids. We found that NPC1L1 knockout (L1-KO) mice fed an HFD had increased energy expenditure, bile acid pool size, and fecal bile acid excretion rates. The elevated bile acid pool in the HFD-fed L1-KO mice was enriched with tauro-β-muricholic acid. These changes in the L1-KO mice were associated with reduced ileal mRNA expression of fibroblast growth factor 15 (FGF15) and increased hepatic mRNA expression of cholesterol 7α-hydroxylase (Cyp7A1) and mitochondrial sterol 27-hydroxylase (Cyp27A1). In addition, mRNA expression of the membrane bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) and type 2 iodothyronine deiodinase (Dio2) were elevated in brown adipose tissue of L1-KO mice, which is known to promote energy expenditure. Thus, altered bile acid homeostasis and signaling may play a role in protecting L1-KO mice against HFD-induced obesity.

Effect of atractylenolide III on interstitial cells of Cajal and C-kit/SCF pathway of rats with loperamide-induced slow transit constipation

Purpose: To determine the effect of atractylenolide-III (ATL-III) on loperamide-induced slow transit constipation (STC) in a rat STC model, and to elucidate the mechanisms involved.&#x0D; Methods: Male Wistar rats were divided into five groups (n=6 per group): normal control group (NG), model group, and three STC rat groups treated with different doses of ATL-III, viz, 5, 10 and 15 mg/kg. The rats were treated for 15 days. Feed consumption, fecal excretion and intestinal transit rate were determined. Nitric oxide synthase (NOS), somatostatin (SS), serotonin (5-HT), and vasoactive intestinal peptide (VIP) were measured with enzyme-linked immunosorbent assay (ELISA). The protein and mRNA expressions of C-kit, SCF, PKC, and PI-3K were assayed using Western blot analysis and realtime reverse transcription polymerase chain reaction (RT-PCR), respectively.&#x0D; Results: The amount, weight, and moisture content of stool, and water consumption were significantly higher in ATL-III-treated groups than in the untreated (model) group (p &lt; 0.05), whereas no difference was observed in feed intake. Intestinal transit rate was higher in the ATL-III-treated groups (p &lt; 0.05). Decreased NOS, SS and VIP levels and increased 5-HT level were seen in the ATL-III-treated groups (p &lt; 0.05). ATL-III treatment also induced increases in smooth muscle cells, neuronal cells, and mucous layer (p&lt;0.05). Results from RT-PCR and Western blot revealed that ATL-III–treated groups had elevated c-kit, SCF, PKC, as well as PI-3K mRNA and protein expressions (p &lt; 0.05).&#x0D; Conclusion: These results suggest that ATL-III mitigates loperamide-induced STC in rats via stimulation of NOS, SS, VIP, and 5-HT secretions. It also increases smooth muscle cells, neuronal cells, and mucous layer, and regulates the signaling pathways involving PKC, PI3K, SCF, and c-kit.

Showcasing the potential of wastewater-based epidemiology to track pharmaceuticals consumption in cities: Comparison against prescription data collected at fine spatial resolution

While the extent of pharmaceutical consumption within a society/community is of high relevance to its health, economy and general wellbeing, this data is often not readily available. Herein, we strengthen a wastewater–based epidemiology (WBE) approach as a way to track the consumption of pharmaceuticals within the sampled community. This method is less laborious than established questionnaire or databases approaches and allows a higher temporal and spatial resolution. The WBE approach was conducted by sampling influent wastewater from two wastewater treatment plants of different size. A total of 39 targeted compounds were quantified by liquid chromatography coupled with tandem mass spectrometry. The number of prescriptions and the defined daily doses for each prescription was obtained from the reference database of The Catalan Health System to validate the wastewater-based approach. The wastewater sampling and the data inquiry were both executed during the same period (October 2019) and standardised for comparison to treatments per 1,000 inhabitants per day. The back-calculation parameters were improved from previous studies by including the faecal excretion rate of the pharmaceuticals. For prescription only pharmaceuticals, where prescription numbers are expected to be a good estimate of consumption, our WBE approach agreed with 27 out of 32 (<0.7 order of magnitude). Common over-the-counter pharmaceuticals such as acetaminophen, ibuprofen and naproxen showed much higher values for treatments per day per 1,000 inhabitant in wastewater than prescribed, reflecting the usefulness of WBE in obtaining an estimate of the total consumption i.e. with and without a prescription.

EOS789, a novel pan-phosphate transporter inhibitor, is effective for the treatment of chronic kidney disease–mineral bone disorder

Chronic kidney disease is characterized as impaired renal function along with the imbalance and dysregulation of mineral metabolism; recognized as chronic kidney disease-mineral and bone disorder. Hyperphosphatemia, characterized by altered phosphate homeostasis along with elevated fibroblast growth factor-23 and intact parathyroid hormone, is such an alteration of mineral metabolism. We discovered a novel inhibitor, EOS789, that interacts with several sodium-dependent phosphate transporters (NaPi-IIb, PiT-1, and PiT-2) known to contribute to intestinal phosphate absorption. This inhibitor dose-dependently increased the fecal phosphorus excretion rate and inversely decreased the urinary phosphorus excretion rate in normal rats, suggesting inhibition of intestinal phosphorus absorption. In rats with adenine-induced hyperphosphatemia, EOS789 markedly decreased the serum phosphate, fibroblast growth factor-23, and intact parathyroid hormone below values found in normal control rats. Notably, this pan-phosphate transporter inhibitor exhibited a more potent effect on serum phosphate than a NaPi-IIb-selective inhibitor in rats with hyperphosphatemia indicating that PiT-1 and PiT-2 play important roles in intestinal phosphate absorption. Moreover, in a long-term study, EOS789 sustained the suppression of serum phosphorus in parallel with fibroblast growth factor-23 and intact parathyroid hormone and ameliorated ectopic calcification of the thoracic aorta. Additionally, EOS789 treatment also ameliorated kidney deterioration in rats with progressive kidney injury, probably due to the strict phosphate control. Thus, EOS789 has potent efficacy against hyperphosphatemia and its complications and could provide a significant benefit to patients who are ineffectively treated with phosphate binders.

Disruption of hepatic small heterodimer partner induces dissociation of steatosis and inflammation in experimental nonalcoholic steatohepatitis

Disruption of hepatic small heterodimer partner induces dissociation of steatosis and inflammation in experimental nonalcoholic steatohepatitis

Predictability of human pharmacokinetics of diisononyl phthalate (DINP) using chimeric mice with humanized liver

1. In order to investigate the pharmacokinetics of diisononyl phthalate (DINP) in humans, we administered [phenyl-U-14C]DINP at a dose of 50.0 mg/kg orally to chimeric mice (humanized-liver mice) in which the liver of TK-NOG mice (control mice) was replaced with human hepatocytes.2. The plasma radioactivity concentrations peaked (18.0 and 59.9 µg equivalent of DINP/mL, respectively) at 2 h after administration in control and humanized-liver mice. Concentrations rose again at 8 h in controls, but not in humanized-liver mice.3. The cumulative excretion rates in urine and feces, respectively, were 58.1% and 37.3% of the doses in controls up to 48 h, but were 86.0% and 7.7% in humanized-liver mice.4. The main circulating metabolites in control and humanized-liver mice were monoisononyl phthalate (MINP) and the glucuronide of oxidized MINP, respectively. The urinary excretion ratio of the glucuronide of oxidized MINP in control mice was one-third of that in humanized-liver mice.5. The present results suggested that the oxidation rates of the primary metabolite of DINP and their excretion routes to urine/feces were different for control and humanized-liver mice. Species differences in liver activities could be a determinant factor in the in vivo metabolism and disposition of diallyl phthalates such as DINP.

Determination of kansuiphorin C and kansuinin A in rat feces using UFLC-MS/MS and its application in the comparative excretion study on normal and malignant ascites rats

Malignant ascites (MA) is one of the severe complications of gastrointestinal tumors, affecting the patients’ survival time and quality of life. Euphorbia kansui is a commonly used toxic Chinese herbal medicine for malignant ascites. Our previous study showed that the biological and toxicological effects of kansui were closely related to the gastrointestinal tract. The ingenane-type and jastrophane-type diterpenoids are both toxic and active components of kansui. The contents of kansuiphorin C (KPC) and kansuinin A (KA) take highest accounts in each type of diterpene. Hence, in this study, the efficacy and toxicity of KPC and KA on normal rats and MA rats were firstly evaluated by serum liver enzymes (ALT and AST), oxidative damage indicators (GSH, SOD, MDA and LDH), inflammatory indexes (TNF-α, IFN-γ and IL-2) and the volume of ascites. Changes in the levels of these indices showed that although the toxicity of KPC on normal rats was stronger than KA, KPC exhibited better efficacy to the malignant ascites with no obvious side effects at the dose of 10 mg·kg−1. Then, accurate and reliable methods for the determination of KPC and KA in the rat feces by ultra-fast liquid chromatography coupled with MS/MS detector (UFLC-MS/MS) were established, detected by the multiple reaction monitoring mode. The chromatographic separation was conducted on an XBbridge C18 column (50 mm × 2.1 mm, 2.5 μm) using gradient elution composed of 0.1% formic acid in water and acetonitrile. The flow rate was 0.5 mL·min−1 and column temperature was 30 °C. The method was finally applied to the comparative study on normal and malignant ascites rats given KPC and KA, respectively. Interestingly, the results showed that KPC’s accumulative fecal excretion rate (normal, 19.22%±5.36%; model, 15.96%±3.47%) were much higher than that of KA (normal, 2.928%±0.741%; model, 2.835%±0.873%) at the same dose within 48 h. This suggested KPC had higher in-vivo transformations in comparison with KA, providing guidance for the further preclinical research of KPC and KA as promising compounds treating MA.

Study of pharmacokinetics and cutaneous photosensitization of hemoporfin in healthy volunteers.

Hemoporfin is a porphyrin-based photosensitizer and has been used for photodynamic therapy of port wine stain birthmarks in China. This study assessed the pharmacokinetics and cutaneous photosensitization of Hemoporfin in healthy volunteers. Sixteen healthy subjects received a single intravenous infusion injection of Hemoporfin (5 mg/kg). The concentrations of Hemoporfin (MHD) and its metabolite Haematoporphyrin (HP) in plasma, urine and faeces were determined. The pharmacokinetic parameters were calculated. In addition, the cutaneous photosensitization was evaluated under the irradiation of solar simulator, 532 nm laser, and sunlight. The Cmax of MHD and HP were 46.7 ± 8.41 and 1.04 ± 0.265 μg/ml, respectively. The t1/2 of MHD and HP were 5.09 ± 0.945 and 5.71 ± 2.65 h, respectively. The AUC0-24h of MHD and HP were 29.8 ± 6.19 and 0.757 ± 0.285 h·μg/ml, respectively. The AUC0-∞ of MHD and HP were 29.8 ± 6.2 and 0.792 ± 0.308 h·μg/ml, respectively. The cumulative fecal excretion rate of MHD and HP were 45.3% and 1.05% at 96 h, respectively. Whereas, the cumulative urinary excretion rate of MHD was only 0.132% at 96 h. The concentration of HP in urine was less than 10% of MHD. After 52 h of administration, the cutaneous photosensitization associated with the exposure to various light sources was minimal. MHD and HP were excreted mainly through the faeces after intravenous infusion. Hemoporfin associated cutaneous photosensitization was insignificant.