Acetaminophen Sulfate Research Articles

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.

Population Pharmacokinetic Modeling and Dose Optimization of Acetaminophen and its Metabolites Following Intravenous Infusion in Critically ill Adults.

Acetaminophen (paracetamol) is a ubiquitously administered drug in critically ill patients. Considering the dearth of literature, we evaluated the population pharmacokinetics of intravenous acetaminophen and its principal metabolites (sulfate and glucuronide) in this population. Critically ill adults receiving intravenous acetaminophen were included in the study. One to three blood samples were withdrawn per patient for the estimation of acetaminophen, and its metabolites (acetaminophen glucuronide and acetaminophen sulfate). High-performance liquid chromatography was used for measuring serum concentrations. We used nonlinear mixed-effect modeling for estimating the primary pharmacokinetic parameters of acetaminophen and its metabolites. The effect of covariates was evaluated followed by dose optimization using Monte Carlo simulation. Patient factors such as demographic information, liver and renal function tests were used as covariates in population pharmacokinetic analysis. The therapeutic range for serum acetaminophen concentration was considered to be 66-132μM, while 990μM was considered as the threshold for toxic concentration. Eighty-seven participants were recruited. A joint two-compartment acetaminophen pharmacokinetic model linked to glucuronide and sulfate metabolite compartments was used. The central and peripheral volume distributions were 7.87 and 8.87 L/70kg, respectively. Estimated clearance (CL) was 0.58L/h/70 kg, while intercompartmental clearance was 44.2L/h/70 kg. The glucuronide and sulfate metabolite CL were 22 and 94.7L/h/70 kg, respectively. Monte Carlo simulation showed that twice-daily administration of acetaminophen would result in a relatively higher proportion of patient population achieving and retaining serum concentrations in the therapeutic range, with reduced risk of concentrations remaining in the toxic range. A joint pharmacokinetic model for intravenous acetaminophen and its principal metabolites in a critically ill patient population has been developed. Acetaminophen CL in this patient population is reduced. We propose a reduction in the frequency of administration to reduce the risk of supra-therapeutic concentrations in this population.

The mechanism of palmatine-mediated intestinal flora and host metabolism intervention in OA-OP comorbidity rats.

ErXian decoction is a Chinese herbal compound that can prevent and control the course of osteoarthritis (OA) and osteoporosis (OP). OP and OA are two age-related diseases that often coexist in elderly individuals, and both are associated with dysregulation of the gut microbiome. In the initial study, Palmatine (PAL) was obtained by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and network pharmacological screening techniques, followed by 16S rRNA sequencing and serum metabolomics of intestinal contents, to explore the mechanism of PAL in the treatment of OA and OP. The rats selected for this study were randomly divided into three groups: a sham group, an OA-OP group and a PAL group. The sham group was intragastrically administered normal saline solution, and the PLA group was treated with PAL for 56 days. Through microcomputed tomography (micro-CT), ELISA, 16S rRNA gene sequencing and non-targeted metabonomics research, we explored the potential mechanism of intestinal microbiota and serum metabolites in PAL treatment of OA-OP rats. Palmatine significantly repair bone microarchitecture of rat femur in OA-OP rats and improved cartilage damage. The analysis of intestinal microflora showed that PAL could also improve the intestinal microflora disorder of OA-OP rats. For example, the abundance of Firmicutes, Bacteroidota, Actinobacteria, Lactobacillus, unclassified_f_Lachnospiraceae, norank_f_Muribaculaceae, Lactobacillaceae, Lachnospiraceae and Muribaculaceae increased after PAL intervention. In addition, the results of metabolomics data analysis showed that PAL also change the metabolic status of OA-OP rats. After PAL intervention, metabolites such as 5-methoxytryptophol, 2-methoxy acetaminophen sulfate, beta-tyrosine, indole-3-carboxylic acid-O-sulfate and cyclodopa glucoside increased. Association analysis of metabolomics and gut microbiota (GM) showed that the communication of multiple flora and different metabolites played an important role in OP and OA. Palmatine can improve cartilage degeneration and bone loss in OA-OP rats. The evidence we provided supports the idea that PAL improves OA-OP by altering GM and serum metabolites. In addition, the application of GM and serum metabolomics correlation analysis provides a new strategy for uncovering the mechanism of herbal treatment for bone diseases.

Comparative Metabolomics Analysis Reveals the Unique Nutritional Characteristics of Breed and Feed on Muscles in Chinese Taihe Black-Bone Silky Fowl.

The Chinese Taihe Black-bone silky fowl (TBsf) is the homology of medicine and food and has high nutritional and medical value all over the world. However, the nutritional compositions and potential metabolite biomarkers of Taihe silky fowl in muscles are still poorly understood. In this study, we investigated the differences in nutritional components between TBsf and another similar breed (Black Feathered chicken and laid green-shelled eggs, BF-gsc). Meanwhile, we also explored the divergences in muscle characteristics of Taihe silky fowl fed with two different diets; that is, normal chicken feed (TBsf-ncf) and Broussonetia papyrifera-fermented feed (TBsf-bpf). Firstly, the growth performance and biochemical index of Taihe silky fowl was significantly different compared with black-feathered chicken. Secondly, we identified the metabolic alterations in Taihe silky fowl by performing an un-targeted UHPLC-Q-TOF-MS/MS analysis. Our results suggested that all the metabonomic characteristics had obvious separation between TBsf-ncf, TBsf-bpf and BF-gsc groups, both in the positive and negative ion mode by PCA analysis. Next, OPLS-DA multivariate analysis revealed that 57 metabolites (in positive mode) and 49 metabolites (in negative mode) were identified as differential metabolites between the TBsf-ncf and BF-gsc groups. These differential metabolites were mainly enriched to ABC transporters, biosynthesis of amino acids and aminoacyl-tRNA biosynthesis. Besides, 47 metabolites (in positive) and 13 metabolites (in negative) were differentially regulated between the TBsf-ncf and TBsf-bpf groups, which were majorly involved in histidine metabolism and linoleic metabolism. Furthermore, the integrated network analysis suggested that DL-arginine, DL-isoleucine, linoleoylcarnitine, stearoylcarnitine (positive) and ricionleic acid, D-proline, and uric acid (negative) were the significant metabolic biomarkers in Taihe silky fowl. Moreover, the metabolites of primaquine, ticlpoidine, riboflavin, acetylcarnitine (positive) and salicylic acid, acetaminophen sulfate, and glutamic acid (negative) were markedly changed in the Taihe silky fowl fed with BP-fermented feed. In summary, a global survey of the nutritional components and metabolite differences was performed in muscle tissues of Taihe silky fowl between various breeds and feeds. Meanwhile, our study provided valuable information for nutritional components and metabolic biomarkers in Chinese Taihe silky fowl, which greatly promoted the economic value of the black-boned chicken industry and laid a solid theoretical foundation for the development of chicken products with greater added value in future.

Evaluation of urinary acetaminophen metabolites and its association with the genetic polymorphisms of the metabolizing enzymes, and serum acetaminophen concentrations in preterm neonates with patent ductus arteriosus

: Acetaminophen is gaining importance as a first-line drug for treating patent ductus arteriosus (PDA) in neonates. Predominant metabolites of acetaminophen in preterm neonates vary from that of adults; and the drug is predominantly metabolized by conjugation and partly by Cytochrome P450 (CYP) enzymes. We carried out the present study to identify the principal urine metabolites of acetaminophen (glucuronide/sulphate) in preterm neonates with hemodynamically significant PDA receiving intravenous acetaminophen, and to evaluate the prevalence of single nucleotide polymorphisms (SNPs) in the key CYP enzymes (CYP1A2*3, CYP1A2*4, CYP1A2*1C, CYP1A2*1K, CYP1A2*6, CYP2D6*10, CYP2E1*2, CYP2E1*5B, CYP3A4*1B, CYP3A4*2, CYP3A4*3, CYP3A5*3, CYP3A5*7, and CYP3A5*11) and their effect on urinary metabolites and serum acetaminophen concentrations. Nineteen (32.8%) neonates had heterozygous CYP1A2*1C, two (3.3%) with heterozygous CYP1A2*1K, 15 (27.8%) and two (3.7%) had heterozygous and homozygous CYP2D6*10, two (3.7%) had heterozygous CYP2E1*5B, seven (12.3%) and three (5.3%) had heterozygous and homozygous CYP3A4*1B, and three (5.5%) had CYP3A5*7 amongst the study population. Acetaminophen sulphate predominated over glucuronide metabolite at all time points. Postnatal days of life was significantly associated with an increase in the urine acetaminophen metabolites with decreased serum acetaminophen concentrations. A significant prevalence of SNPs in the key CYP enzymes related to acetaminophen metabolism was observed in our neonatal population. Population pharmacokinetic-pharmacodynamic modeling incorporating genetic and metabolite data is urgently needed for implementation of precision medicine in this vulnerable population.

Application of tail vein serial microsampling for plasma or dried plasma spots in toxicokinetic assessment in rats using acetaminophen as the model compound.

In the current study, two groups of rats (five per group) were administered a single oral dose of 500 mg/kg acetaminophen. For toxicokinetic assessment, the Group 1 animals were bled via conventional sparse (two animals/time point) sublingual vein bleeding (~0.5 ml) with anesthesia, while the Group 2 animals were bled via serial tail vein microsampling (~0.075 ml) without anesthesia. All collected blood was processed for plasma. Each Group 2 plasma sample (~30 μl) was divided into 'wet' and 'dried' (dried plasma spots). All plasma samples were analyzed by LC-MS/MS for acetaminophen and its major metabolites acetaminophen glucuronide and acetaminophen sulfate. In addition, plasma and urine samples were collected for analysis of corticosterone and creatinine to assess stress levels. Comparable plasma exposure to acetaminophen and its two metabolites was observed in the plasma obtained via conventional sparse sublingual vein bleeding and serial tail vein microsampling and between the 'wet' and 'dried' plasma obtained by the latter. Furthermore, comparable corticosterone levels or corticosterone/creatinine ratios between the two groups suggested that serial microsampling without anesthesia did not increase the levels of stress as compared with conventional sampling with anesthesia, confirming the utility of microsampling for plasma or dried plasma spots in rodent toxicokinetic assessment.

Determination of acetaminophen and its main metabolites in urine by capillary electrophoresis hyphenated to mass spectrometry

In this study, a capillary electrophoresis-tandem mass spectrometry method combining efficient separation and sensitive detection has been developed and validated, for the first time, to quantify acetaminophen and five of its metabolites in urine samples. Optimization of the method has led us to perform detection in positive ESI mode using MeOH-ammonium hydroxide (0.1%) (50:50, v/v) as sheath liquid. Moreover, optimal separation has been obtained in less than 9 min after anodic injection, using an ammonium acetate solution (40 mM, pH 10) as BGE. It was shown that the dilution solvent and the dilution factor to use for sample preparation are critical parameters to avoid peak splitting, to gain in sensitivity and then to obtain an effective analysis method. While a 200-fold factor dilution was shown to be suitable for quantitation of acetaminophen, acetaminophen mercapturate, acetaminophen sulfate and acetaminophen glucuronide, a 20-fold dilution was finally selected for methoxy-acetaminophen and 3-methylthioacetaminophen analysis, thus requiring two successive analyses to be carried out in order to quantify all metabolites. Hyphenation of CE with MS/MS versus UV permits to improve LOQ (10–20-fold factor with respect to previous works for acetaminophen, acetaminophen sulfate and acetaminophen glucuronide). Moreover, use of CE versus HPLC, permits to quantify two additional metabolites, i.e. 3-methylthio-acetaminophen and methoxy-acetaminophen. The method has been validated using the accuracy profile approach with a total error (accuracy) included in the ± 20% range. Thereby, the method allows the quantitation of acetaminophen and acetaminophen mercapturate in the range (0.1–1 mg mL-1), and of acetaminophen sulfate, methoxy-acetaminophen, acetaminophen glutathione and 3-methylthio-acetaminophen in the ranges (0.5–5 mg mL-1), (0.025–0.4 mg mL-1), (9.22–30 mg mL-1) and (0.073–0.4 mg mL-1), respectively. The method was finally applied to the analysis of urine samples of eighteen patients belonging to three different inclusion groups of the ongoing clinical trial, demonstrating that the method is suitable to highlight different metabolic profiles. This work will be subsequently extended to the analysis two hundred and seventy urine samples from patients included in a clinical trial dedicated to the study of acetaminophen metabolism changes after hepatic resection.

Population Pharmacokinetic Modeling of Acetaminophen and Metabolites in Children After Cardiac Surgery With Cardiopulmonary Bypass.

Children undergoing cardiac surgery often receive acetaminophen (paracetamol) as part of their postoperative pain treatment. To date, there is no information on the pharmacokinetics (PK) of acetaminophen in this special population, even though differences, as a result of altered hemodynamics and/or use of cardiopulmonary bypass, may be anticipated. Therefore, the aim of this study was to investigate the PK of intravenous acetaminophen in children after cardiac surgery with cardiopulmonary bypass. In the study, both children with and without Down syndrome were included. A population PK analysis, using NONMEM 7.2, was performed based on 161 concentrations of acetaminophen, acetaminophen sulfate, acetaminophen glucuronide, and oxidative metabolites from 17 children with Down syndrome and 13 children without Down syndrome of a previously published study (median age, 177 days [range, 92–944], body weight, 6.1 kg [4.0–12.9]). All children received 3 intravenous acetaminophen doses of 7.5 mg/kg (<10 kg) or 15 mg/kg (≥10 kg) at 8–hour intervals after cardiac surgery. For acetaminophen and its metabolites, 1‐compartment models were identified. Clearance of acetaminophen and metabolites increased linearly with body weight. Acetaminophen clearance in a typical child of 6.1 kg is 0.96 L/h and volume of distribution 7.96 L. Down syndrome did not statistically significantly impact any of the PK parameters for acetaminophen, nor did any other remaining covariate. When comparing the PK parameters of acetaminophen in children after cardiac surgery with cardiopulmonary bypass with those from children of the same age following noncardiac surgery reported in the literature, clearance of acetaminophen was lower and volume of distribution higher.

Effects of the human SULT1A1 polymorphisms on the sulfation of acetaminophen,O-desmethylnaproxen, and tapentadol.

Non-opioid and opioid analgesics, as over-the-counter or prescribed medications, are widely used for the management of a diverse array of pathophysiological conditions. Previous studies have demonstrated the involvement of human cytosolic sulfotransferase (SULT) SULT1A1 in the sulfation of acetaminophen, O-desmethylnaproxen (O-DMN), and tapentadol. The current study was designed to investigate the impact of single nucleotide polymorphisms (SNPs) of the human SULT1A1 gene on the sulfation of these analgesic compounds by SULT1A1 allozymes. Human SULT1A1 genotypes were identified by database search. cDNAs corresponding to nine SULT1A1 nonsynonymous missense coding SNPs (cSNPs) were generated by site-directed mutagenesis. Recombinant wild-type and SULT1A1 allozymes were bacterially expressed and affinity-purified. Purified SULT1A1 allozymes were analyzed for sulfation activity using an established assay procedure. Compared with the wild-type enzyme, SULT1A1 allozymes were shown to display differential sulfating activities toward three analgesic compounds, acetaminophen, O-desmethylnaproxen (O-DMN), and tapentadol, as well as the prototype substrate 4NP. Results obtained indicated clearly the impact of genetic polymorphisms on the drug-sulfation activity of SULT1A1 allozymes. Such information may contribute to a better understanding about the differential metabolism of acetaminophen, O-DMN, and tapentadol in individuals with different SULT1A1 genotypes.

Environmental fate of pharmaceutical compounds and antimicrobial-resistant bacteria in hospital effluents, and contributions to pollutant loads in the surface waters in Japan

Environmental fate of 58 pharmaceutical compounds (PhCs) grouped into 11 therapeutic classes in the three different waters, hospital effluent, sewage treatment plant (STP) and river water, was estimated by combination of their quantitative concentration analysis and evaluation of their extent of contribution as loading sources. At the same time, distribution of six classes of antimicrobial-resistant bacteria (AMRB) in the same water samples was estimated by screening of individual PhC-resistant microbes grown on each specific chromogenic medium. The results indicate that 48 PhCs were detected ranged from 1 ng/L (losartan carboxylic acid) to 228 μg/L (acetaminophen sulfate) in hospital effluent, and contribution of the pollution load derived from hospital effluent to STP influent was estimated as 0.1% to 15%. On the other hand, contribution of STP effluent to river water was high, 32% to 60% for antibacterials, antipertensives and X-ray contrast media. In the cases for AMRB, detected numbers of colonies of AMRB in hospital effluent ranged from 29 CFU/mL to 1805 CFU/mL, and the estimated contribution of the AMRB pollution load derived from hospital effluent to STP influent was as low as 0.1% (levofloxacin and olmesartan) to 5.1% (N-desmethyl tamoxifen). Although the contribution of STPs as loading sources of PhCs and AMRB in surface waters was large, ozonation as an advanced water treatment system effectively removed a wide range of both PhCs and AMRB in water samples. These results suggest the importance of reducing environmental pollutant loads (not only at STPs but also at medical facilities) before being discharged into the surface waters, to both conserve water and keep the water environment safe. To our knowledge, this is the first report to show the distribution and contribution of AMRB from hospital effluent to the surface waters.

Effects of human SULT1A3/SULT1A4 genetic polymorphisms on the sulfation of acetaminophen and opioid drugs by the cytosolic sulfotransferase SULT1A3

Sulfoconjugation has been shown to be critically involved in the metabolism of acetaminophen (APAP), morphine, tapentadol and O-desmethyl tramadol (O-DMT). The objective of this study was to investigate the effects of single nucleotide polymorphisms (SNPs) of human SULT1A3 and SULT1A4 genes on the sulfating activity of SULT1A3 allozymes toward these analgesic compounds. Twelve non-synonymous coding SNPs (cSNPs) of SULT1A3/SULT1A4 were investigated, and the corresponding cDNAs were generated by site-directed mutagenesis. SULT1A3 allozymes, bacterially expressed and purified, exhibited differential sulfating activity toward each of the four analgesic compounds tested as substrates. Kinetic analyses of SULT1A3 allozymes further revealed significant differences in binding affinity and catalytic activity toward the four analgesic compounds. Collectively, the results derived from the current study showed clearly the impact of cSNPs of the coding genes, SULT1A3 and SULT1A4, on the sulfating activity of the coded SULT1A3 allozymes toward the tested analgesic compounds. These findings may have implications in the pharmacokinetics as well as the toxicity profiles of these analgesics administered in individuals with distinct SULT1A3 and/or SULT1A4 genotypes.

Race, Gender, and Genetic Polymorphism Contribute to Variability in Acetaminophen Pharmacokinetics, Metabolism, and Protein-Adduct Concentrations in Healthy African-American and European-American Volunteers.

Over 30 years ago, black Africans from Kenya and Ghana were shown to metabolize acetaminophen faster by glucuronidation and slower by oxidation compared with white Scottish Europeans. The objectives of this study were to determine whether similar differences exist between African-Americans and European-Americans, and to identify genetic polymorphisms that could explain these potential differences. Acetaminophen plasma pharmacokinetics and partial urinary metabolite clearances via glucuronidation, sulfation, and oxidation were determined in healthy African-Americans (18 men, 23 women) and European-Americans (34 men, 20 women) following a 1-g oral dose. There were no differences in acetaminophen total plasma, glucuronidation, or sulfation clearance values between African-Americans and European-Americans. However, median oxidation clearance was 37% lower in African-Americans versus European-Americans (0.57 versus 0.90 ml/min per kilogram; P = 0.0001). Although acetaminophen total or metabolite clearance values were not different between genders, shorter plasma half-life values (by 11-14%; P < 0.01) were observed for acetaminophen, acetaminophen glucuronide, and acetaminophen sulfate in women versus men. The UGT2B15*2 polymorphism was associated with variant-allele-number proportional reductions in acetaminophen total clearance (by 15-27%; P < 0.001) and glucuronidation partial clearance (by 23-48%; P < 0.001). UGT2B15 *2/*2 genotype subjects also showed higher acetaminophen protein-adduct concentrations than *1/*2 (by 42%; P = 0.003) and *1/*1 (by 41%; P = 0.003) individuals. Finally, CYP2E1 *1D/*1D genotype African-Americans had lower oxidation clearance than *1C/*1D (by 42%; P = 0.041) and *1C/*1C (by 44%; P = 0.048) African-Americans. Consequently, African-Americans oxidize acetaminophen more slowly than European-Americans, which may be partially explained by the CYP2E1*1D polymorphism. UGT2B15*2 influences acetaminophen pharmacokinetics in both African-Americans and European-Americans.

A method for evaluating the pharmaceutical deconjugation potential in river water environments

A new enzymatic assay method that uses deconjugation enzymes was developed to evaluate the presence and extent of conjugated pharmaceuticals in the form of glucuronide conjugates or sulphate conjugates in river environments. First, acetaminophen glucuronide (Ace Glu) and acetaminophen sulphate (Ace Sul) were used as model conjugated pharmaceuticals to determine the appropriate combination of deconjugation enzymes and reaction conditions, including temperature, duration and pH. Next, we applied the defined method to 19 pharmaceuticals grouped into nine therapeutic classes that were chosen based on previously detected levels and frequencies in sewage and river water. The enzymatic decomposition profile varied widely depending upon the enzyme preparations available. The effect of the water reaction temperature was small between 5 and 40 °C, and the reaction proceeded in for both glucuronide conjugates and sulphate conjugates at an approximately neutral pH (corresponding to usual river water conditions) within 1 h. Application of the method to environmental samples showed that some pharmaceuticals were present in both glucuronide conjugate and sulphate conjugated forms, although glucuronide conjugates were the primary forms in the river water environment. Water treatment systems at sewage treatment plants were found to be effective for the removal of these conjugated compounds. The present results should be valuable in the environmental risk assessment of conjugated pharmaceuticals and in keeping river environments clean. To the best of our knowledge, this is the first report that enables the evaluation of the pharmaceutical deconjugation potential in a river environment.

Quantitative Method for Simultaneous Analysis of Acetaminophen and 6 Metabolites

Hepatotoxicity after ingestion of high-dose acetaminophen [N-acetyl-para-aminophenol (APAP)] is caused by the metabolites of the drug. To gain more insight into factors influencing susceptibility to APAP hepatotoxicity, quantification of APAP and metabolites is important. A few methods have been developed to simultaneously quantify APAP and its most important metabolites. However, these methods require a comprehensive sample preparation and long run times. The aim of this study was to develop and validate a simplified, but sensitive method for the simultaneous quantification of acetaminophen, the main metabolites acetaminophen glucuronide and acetaminophen sulfate, and 4 Cytochrome P450-mediated metabolites by using liquid chromatography with mass spectrometric (LC-MS) detection. The method was developed and validated for the human plasma, and it entailed a single method for sample preparation, enabling quick processing of the samples followed by an LC-MS method with a chromatographic run time of 9 minutes. The method was validated for selectivity, linearity, accuracy, imprecision, dilution integrity, recovery, process efficiency, ionization efficiency, and carryover effect. The method showed good selectivity without matrix interferences. For all analytes, the mean process efficiency was >86%, and the mean ionization efficiency was >94%. Furthermore, the accuracy was between 90.3% and 112% for all analytes, and the within- and between-run imprecision were <20% for the lower limit of quantification and <14.3% for the middle level and upper limit of quantification. The method presented here enables the simultaneous quantification of APAP and 6 of its metabolites. It is less time consuming than previously reported methods because it requires only a single and simple method for the sample preparation followed by an LC-MS method with a short run time. Therefore, this analytical method provides a useful method for both clinical and research purposes.

Detection of pharmaceuticals and phytochemicals together with their metabolites in hospital effluents in Japan, and their contribution to sewage treatment plant influents

The occurrence of 41 pharmaceuticals and phytochemicals (PPs) including their metabolites was surveyed in hospital effluent in an urban area of Japan. A detailed survey of sewage treatment plant (STP) influent and effluent, and river water was also conducted. Finally, mass balances with mass fluxes of the target PPs through the water flow were evaluated and the degree of contribution of hospital effluent to the environmental discharge was estimated.The results indicate that 38 compounds were detectable in hospital effluent over a wide concentration range from ng/L to μg/L, with a maximum of 92μg/L. The contributions of PPs in the hospital effluent to STP influent varied widely from <0.1% to 14.8%. Although almost all of the remaining components could be removed below 1.0ng/L at STPs by the addition of ozone treatment, a number of PPs still remained above 10ng/L in STP effluent.These findings suggest the importance of applying highly developed treatments to hospital effluents and at STPs in the future to reduce the environmental risks posed by PPs. To our knowledge, this is the first demonstration of the presence of two conjugated metabolites of acetaminophen, acetaminophen glucuronide and acetaminophen sulfate, as well as of loxoprofen and loxoprofen alcohol, in hospital effluent, STP, and river waters.

Favipiravir inhibits acetaminophen sulfate formation but minimally affects systemic pharmacokinetics of acetaminophen

AimsThe antiviral agent favipiravir is likely to be co-prescribed with acetaminophen (paracetamol). The present study evaluated the possiblility of a pharmacokinetic interaction between favipiravir and acetaminophen, in vitro and in vivo.MethodsThe effect of favipivir on the transformation of acetaminophen to its glucuronide and sulfate metabolites was studied using a pooled human hepatic S9 fraction in vitro. The effect of acute and extended adminstration of favipiravir on the pharmacokinetics of acetaminophen and metabolites was evaluated in human volunteers.ResultsFavipiravir inhibited the in vitro formation of acetaminophen sulfate, but not acetaminophen glucuronide. In human volunteers, both acute (1 day) and extended (6 days) administration of favipiravir slightly but significantly increased (by about 20 %) systemic exposure to acetaminophen (total AUC), whereas Cmax was not significantly changed. AUC for acetaminophen glucuronide was increased by 23 to 35 % above control by favipiravir, while AUC for acetaminophen sulfate was reduced by about 20 % compared to control. Urinary excretion of acetaminophen sulfate was likewise reduced to 44 to 65 % of control values during favipiravir co-administration, while excretion of acetaminophen glucuronide increased to 17 to 32 % above control.ConclusionFavipiravir inhibits acetaminophen sulfate formation in vitro and in vivo. However the increase in systemic exposure to acetaminophen due to favipiravir co-administration, though statistically significant, is small in magnitude and unlikely to be of clinical importance.

Population pharmacokinetics of intravenous acetaminophen and its metabolites in major surgical patients.

Intravenous acetaminophen is a commonly used analgesic following surgery. The aims of this study were to determine the population pharmacokinetic profile of intravenous acetaminophen and its metabolites in adult surgical patients and to identify patient characteristics associated with acetaminophen metabolism in the postoperative period. 53 patients were included in the dataset; 28 were men, median age (range) 60years(33-87), median weight (range) 74kg (54-129). Patients received 1, 1.5 or 2g of intravenous acetaminophen every 4-6h. Plasma and urine samples were collected at various intervals for up to 6days after surgery. Simultaneous modelling of parent acetaminophen and its metabolites was conducted in Phoenix(®) NLME™ to estimate pharmacokinetic parameters. The population mean estimate (CV%) for central (plasma) volume of distribution of parent acetaminophen (VC) was 13.9 (4.41) L, peripheral (tissue) volume of distribution (VT) was50.9(2.96)L, and intercompartmental clearance (Q) was77.5(9.29)L/h. The population mean (CV%) metabolic clearances for glucuronidation (CLPG) was 8.92 (3.25)L/h, sulfation (CLPS) was 0.903(3.47)L/h, and oxidation (CLPO) was 0.533(7.90)L/h. The population mean (CV%) urinary clearances of parent acetaminophen (CLRP) was 0.137(5.46)L/h, acetaminophen glucuronide (CLRG) was 3.81(6.71)L/h, acetaminophen sulfate (CLRS) was 3.13 (4.32)L/h, and acetaminophen cysteine+mercapturate (CLRO) was 3.51 (9.98)L/h. Age was found to be a significant covariate on the formation of acetaminophen glucuronide, and renal function (estimated as creatinine clearance) on the urinary excretion of acetaminophen glucuronide.

Regulation of Hepatic Phase II Metabolism in Pregnant Mice

Phase II enzymes, including Ugts, Sults, and Gsts, are critical for the disposition and detoxification of endo- and xenobiotics. In this study, the mRNA and protein expression of major phase II enzymes, as well as key regulatory transcription factors, were quantified in livers of time-matched pregnant and virgin control C57BL/6 mice on gestation days (GD) 7, 11, 14, 17, and postnatal days (PND) 1, 15, and 30. Compared with virgin controls, the mRNA expression of Ugt1a1, 1a6, 1a9, 2a3, 2b1, 2b34, and 2b35 decreased 40 to 80% in pregnant dams. Protein expression of Ugt1a6 also decreased and corresponded with reduced in vitro glucuronidation of bisphenol A in S9 fractions from livers of pregnant mice. Similar to Ugts levels, Gsta1 and a4 mRNAs were reduced in pregnant dams in mid to late gestation; however no change in protein expression was observed. Conversely, Sult1a1, 2a1/2, and 3a1 mRNAs increased 100 to 500% at various time points in pregnant and lactating mice and corresponded with enhanced in vitro sulfation of acetaminophen in liver S9 fractions. Coinciding with maximal decreases in Ugts as well as increases in Sults, the expression of transcription factors CAR, PPARα, and PXR and their target genes were downregulated, whereas ERα mRNA was upregulated. Collectively, these data demonstrate altered regulation of hepatic phase II metabolism in mice during pregnancy and suggest that CAR, PPARα, PXR, and ERα signaling pathways may be candidate signaling pathways responsible for these changes.

Evaluating human liver reserve function by measuring serum concentrations of phenacetin and its metabolites

To evaluate human liver reserve function (LRF) by a simple and efficient method for measuring serum concentrations of phenacetin and its metabolites. Overall 20 patients with liver cirrhosis (Child-Pugh score ≥ 7, aged 48-79 years), 30 healthy young volunteers (aged 18-40 years), and 20 healthy elderly volunteers (aged 61-80 years) were enrolled. All participants received a single oral dose of 0.5 g phenacetin. Liquid chromatography tandem mass spectrometry was used to determine the serum concentrations of phenacetin and its metabolites, including acetaminophen, acetaminophen glucuronide and acetaminophen sulfate. The serum concentration of phenacetin was significantly higher in cirrhotic patients than those in either of the healthy volunteer groups (P < 0.001). It was higher in healthy elderly volunteers than that in healthy young ones but there was no statistically significant difference (P > 0.05) between them. The serum concentrations of acetaminophen, acetaminophen glucuronide and acetaminophen sulfate were significantly lower in cirrhotic patients than in the healthy controls (P < 0.001). The serum concentrations of these three metabolites in healthy elderly volunteers were lower than those in healthy younger volunteers but again, there was no statistical significant difference (P > 0.05). The serum concentration of acetaminophen in healthy male volunteers was significantly higher than that in the women (P < 0.05). Monitoring cytochrome P450 1A2 (CYP450 1A2)-mediated phenacetin metabolism is a simple and efficient method for evaluating human LRF. This method would warrant further validation in a large cohort clinical study.

Phase II pharmaceutical metabolites acetaminophen glucuronide and acetaminophen sulfate in wastewater

Environmental context. Excretion of pharmaceuticals and their metabolites by humans and animals, flushing unused pharmaceuticals and inadequate water treatment result in the occurrence of these chemicals as pollutants in wastewater, surface water and drinking water. In this research, the pharmaceutical agent acetaminophen (paracetamol, Tylenol) and its glucuronide and sulfate metabolites were examined as a model system for monitoring wastewater influent and effluent. The true risk to ecosystems and humans from the occurrence of pharmaceuticals in our water supply can only be estimated if accurate concentrations of parent pharmaceutical chemicals as well as their metabolites are measured. Abstract. An analytical method was developed to separately determine acetaminophen and its Phase II metabolites, acetaminophen glucuronide and acetaminophen sulfate, from wastewater in a single extract. The method developed will serve as a model for screening for the presence of other non-steroidal pharmaceutical compounds and their Phase II metabolites in wastewater. Acetaminophen glucuronide was not present in the wastewater influent tested to verify the analytical protocol, whereas concentrations of acetaminophen and acetaminophen sulfate in the influent were reproducible over time. A Phase I metabolite, p-aminophenol, was also determined to occur in the wastewater influent. Concentrations of the analytes-of-interest, detected in effluent samples collected after secondary treatment, but before UV treatment, were highly variable and were undetectable after UV treatment before release to surface water.