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Aims: Our aim was to describe the pharmacokinetics of paracetamol and its metabolites in extreme preterm neonates in the context of patent ductus arteriosus treatment. Factors associated with inter-individual variability and metabolic pathways were studied. The association between drug exposure and clinical outcomes were investigated., Methods: Preterm neonates of 23-26 weeks' gestational age received paracetamol within 12 h after birth. Plasma concentrations of paracetamol and its metabolites were measured throughout 5 days of treatment. Clinical success was defined as ductus closure on two consecutive days or at day 7. Aspartate aminotransferase and alanine aminotransferase levels were used as surrogates for liver damage., Results: Data from 30 preterm neonates were available for pharmacokinetic analysis. Paracetamol pharmacokinetics were described using a two-compartment model with significant positive effects of weight on clearance and of birth length on peripheral compartment volume. Paracetamol was mainly metabolised into sulphate (89%) then glucuronide (6%), and the oxidative metabolic pathway was reduced (4%). The glucuronidation pathway increased with gestational age, whereas the sulfation pathway decreased. No difference was observed in drug exposure between successful and unsuccessful patients. No increase in aspartate aminotransferase and alanine aminotransferase levels were observed during treatment, and no association was found with either paracetamol or oxidative metabolite exposures., Conclusion: The relative proportions of the metabolic pathways were characterised with gestational age. In the range of observed drug exposures, no association was found with clinical response or liver biomarkers. These findings may suggest that paracetamol concentrations were within the range that already guarantee a maximum effect on ductus closure., Competing Interests: Declarations. Funding: Institut national de la santé et de la recherche médicale (Inserm) is the sponsor of the TREOCAPA trial. The project leading to this application has received funding through the Connect4Children consortium from the Innovative Medicines Initiatives 2 Joint Undertaking under grant agreement n°777389. This joint undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. Role of the funder/sponsor: The funding organisation had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. Conflict of interest: Faheemah Padavia, Jean-Marc Treluyer, Gilles Cambonie, Cyril Flamant, Aline Rideau, Manon Tauzin, Juliana Patkai, Géraldine Gascoin, Mirka Lumia, Outi Aikio, Frantz Foissac, Saïk Urien, Sihem Benaboud, Gabrielle Lui, Léo Froelicher Bournaud, Yi Zheng, Ruth Kemper, Marine Tortigue, Alban-Elouen Baruteau, Jaana Kallio, Mikko Hallman, Alpha Diallo, Léa Levoyer, Jean-Christophe Roze And Naïm Bouazza declare that they have no potential conflicts of interest that might be relevant to the contents of this manuscript. Ethics approval: The trial was approved by the ethics committee of Centre Hospitalier La Chartreuse (approval number SI 20.03.09.40128) for France and by the regional medical research ethics committee of North Ostrobothnia (approval number 68/06.00.00/20 19) for Finland. Consent to participate: Written informed consent was obtained from both parents of each infant. Consent for publication: Not applicable. Data availability statement: The data that support the findings of this study are available from Institut national de la santé et de la recherche médicale (Inserm) but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. However, data are available from the authors upon reasonable request and with permission from Inserm. Author contributions: Concept and design: NB, MH, JMT, JCR. Acquisition of data: GC, CF, AR, MT, JP, GG, ML, OA, YZ, MT, AEB. Analysis and interpretation of data: FP, NB, FF, SU, JCR. Drafting of the manuscript: FP, NB, FF, SU, GL, LFB, JCR. Critical revision of the manuscript for important intellectual content: All authors., (© 2024. The Author(s).)

Background and Aims: Acetaminophen (APAP) hepatotoxicity and ischemic hepatic injury (IH) demonstrate remarkably similar biochemical patterns. Deciding between these two etiologies in the setting of acute liver failure (ALF) can be challenging. We reviewed all cases in the Acute Liver Failure Study Group (ALFSG) registry where these diagnoses were considered, to determine reasons for, and frequency of, difficulties making these diagnoses. We hypothesized that the newly developed APAP-CYS adduct assay could help in discerning the correct diagnosis., Methods: Among 3364 patients with ALF or acute liver injury (ALI: INR ≥ 2.0 but without encephalopathy) between 1998 and 2019, 1952 (58%) received a final diagnosis of either APAP (1681) or IH (271). We utilized a review committee of senior hepatologists as well as the APAP-CYS assay (where sera were available), measuring the presence of toxic by-products of APAP injury to optimize adjudication., Results: With these methods, a total of 575 adduct positive APAP cases included 488 recognized APAP, as well as an additional 87 patients previously diagnosed as other etiologies. Nine cases initially attributed to IH were deemed combination APAP-IH injuries. Conversely, 215 of the 280 IH subjects tested for adducts disclosed 173 confirmed as IH with adduct testing below the toxicity threshold, while 9 cases were revised from APAP to the IH-APAP combination phenotype, where both hypotension and APAP likely played a role., Conclusions: Discerning APAP from IH can be difficult-in rare cases, combined injury is observed (18/1952). APAP-CYS testing resulted in revising the diagnosis in 14.6% of cases., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Nefopam and propacetamol are the most commonly used analgesics in postoperative multimodal analgesic regimens. Distinct mechanisms are involved in each drug's anti-nociceptive effects. No studies have compared pain relief efficacy between the two drugs in patients undergoing transplantation surgery. Here, we investigated whether the administration of nefopam or propacetamol to healthy living kidney donors who underwent rectus sheath block (RSB) for parietal pain could reduce the subsequent opioid dose necessary to produce adequate analgesia., Methods: This prospective, randomized controlled trial included 72 donors undergoing elective hand-assisted living donor nephrectomy into two groups: propacetamol (n = 36) and nefopam (n = 36). Intraoperative RSB was performed in all enrolled donors. The primary outcome was the total volume of intravenous opioid-based patient-controlled analgesia (PCA) used on postoperative day 1 (POD 1). Additionally, the Numeric Rating Scale scores for flank (visceral) and umbilicus (parietal) pain at rest and during coughing were compared, and the Korean adaptation of the Quality of Recovery-15 Questionnaire (QoR-15 K) was evaluated on POD 1., Results: Both groups had similar preoperative and intraoperative characteristics. On POD 1, the total amount of PCA infusion was significantly lower in the nefopam group than in the propacetamol group (44.5 ± 19.3 mL vs. 70.2 ± 29.0 mL; p < 0.001). This group also reported lower pain scores at the flank and umbilical sites and required fewer rescue doses of fentanyl in the post-anesthesia care unit. However, pain scores and fentanyl consumption in the ward were comparable between groups. The QoR-15 K scores were similar between groups; there were substantial improvements in breathing, pain severity, and anxiety/depression levels in the nefopam group. The incidences of postoperative complications, including sweating and tachycardia, were similar between groups., Conclusion: Compared with propacetamol, nefopam provides a greater analgesic effect for visceral pain and enhances the effects of blocks that reduce the opioid requirement in living kidney donors with parietal pain managed by RSB., Trial Registration: The trial was registered prior to patient enrollment in the clinical trial database using the Clinical Research Information Service (registration no. KCT0007351 , Date of registration 03/06/2022)., (© 2024. The Author(s).)

Background: Previous studies have linked prenatal acetaminophen use to increased asthma risk in children. However, none have explored this association while differentiating between asthma cases with and without other allergic conditions or by employing objective biomarkers to assess acetaminophen exposure., Objective: To evaluate whether the detection of acetaminophen biomarkers in cord blood is associated with the subgroups of asthma both with and without allergic comorbidities in children., Methods: Acetaminophen biomarkers, including unchanged acetaminophen and acetaminophen glucuronide, were measured in neonatal cord blood samples from the Boston Birth Cohort. Asthma subgroups were defined on the basis of physician diagnoses of asthma and other allergic conditions (atopic dermatitis and allergic rhinitis). Multinomial regressions were used to evaluate the associations between acetaminophen biomarkers and asthma subgroups, adjusting for multiple confounders, including potential indications for maternal acetaminophen use such as maternal fever., Results: The study included 142 children with asthma and at least 1 other allergic condition, 55 children with asthma but no other allergic condition, and 613 children free of asthma. Detection of acetaminophen in cord blood, reflecting maternal exposure to acetaminophen shortly before delivery, was associated with 3.73 times the odds of developing asthma without allergic comorbidities (95% CI: 1.79-7.80, P = .0004). In contrast, the detection of acetaminophen in cord blood was not associated with an elevated risk of asthma with allergic comorbidities. Analysis of acetaminophen glucuronide yielded consistent results., Conclusion: In a prospective birth cohort, cord blood acetaminophen biomarkers were associated with an increased risk of childhood asthma without allergic comorbidities, but were not associated with childhood asthma with allergic comorbidities., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Intravenous propacetamol is commonly used to control fever and pain in neurocritically ill patients in whom oral administration is often difficult. However, several studies reported that intravenous propacetamol may cause blood pressure drop. Thus, we aimed to investigate the occurrence and risk factors for intravenous propacetamol-induced blood pressure drop in neurocritically ill patients., Methods: This retrospective study included consecutive patients who were administered intravenous propacetamol in a neurointensive care unit at a single tertiary academic hospital between April 2013 and June 2020. The exact timing of intravenous propacetamol administration was collected from a database of the electronic barcode medication administration system. Blood pressure drop was defined as a systolic blood pressure below 90 mm Hg or a decrease by 30 mm Hg or more. Blood pressure, pulse rate, and body temperature were collected at baseline and within 2 h after intravenous propacetamol administration. The incidence of blood pressure drop was evaluated, and multivariable logistic regression analysis was performed to identify risk factors for blood pressure drop events., Results: A total of 16,586 instances of intravenous propacetamol administration in 4916 patients were eligible for this study. Intravenous propacetamol resulted in a significant decrease in systolic blood pressure (baseline 131.1 ± 17.8 mm Hg; within 1 h 124.6 ± 17.3 mm Hg; between 1 and 2 h 123.4 ± 17.4 mm Hg; P < 0.01). The incidence of blood pressure drop events was 13.5% within 2 h after intravenous propacetamol. Older age, lower or higher baseline systolic blood pressure, fever, higher Acute Physiology and Chronic Health Evaluation II score, and concomitant administration of vasopressors/inotropes or analgesics/sedatives were significant factors associated with the occurrence of blood pressure drop events after intravenous propacetamol administration., Conclusions: Intravenous propacetamol can induce hemodynamic changes and blood pressure drop events in neurocritically ill patients. This study identified the risk factors for blood pressure drop events. On the basis of our results, judicious use of intravenous propacetamol is warranted for neurocritically ill patients with risk factors that make them more susceptible to hemodynamic changes., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Acetaminophen (APAP)-induced liver injury (AILI) is the most common cause of acute liver failure. Although the mechanisms that trigger AILI are well known, it is less understood how to halt AILI progression and facilitate liver recovery. Therefore, it is necessary to understand the pathophysiology of APAP hepatotoxicity in patients and to examine predictive/preventive markers. In a clinical study, we had a case in which aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels increased in a patient with a low ratio of APAP glucuronide concentration (AP-G)/APAP plasma concentration. Then a reverse translational study was conducted for clarifying this clinical question. The relationship between plasma AP-G/APAP concentration ratio and the levels of AST and ALT was examined by in vivo and in vitro experiments. In in vivo experiments, 10-week-old rats showed lower UGT activity, lower AP-G/APAP concentration ratios, and higher AST and ALT levels than 5-week-old rats. This suggests an inverse correlation between the AP-G/APAP concentration ratio and the AST, ALT levels in APAP-treated rats. Furthermore, as a result of the in vitro experiment, it was confirmed that the cell viability decreased when the AP-G/APAP concentration ratio in the culture medium decreased. Since the decrease in the plasma AP-G/APAP concentration ratio appears earlier than the increase of AST and ALT levels, the ratio might be a presymptomatic marker of AILI. When APAP is used for a long time, it is recommended to perform therapeutic drug monitoring of the AP-G/APAP concentration ratio, which is a predictive/preventive marker of AILI., (© 2022 John Wiley & Sons Ltd.)

Propacetamol is a prodrug form of paracetamol (APAP) licensed for human use as a pain reliever in postoperative care. It is prescribed if APAP cannot be administered orally or rectally to a patient and for patients in whom nonsteroidal anti-inflammatory drugs are contraindicated. In this study, we aimed to quantify the pharmacokinetics of APAP and its metabolites, paracetamol sulfate (PS), paracetamol glucuronide (PG), and N-acetyl-p-benzoquinone imine (NAPQI), after a single oral and intravenous (IV) administration of 30 mg/kg of propacetamol to six healthy adult Labrador dogs according to a 2 × 2 crossover study. The analyses were performed using a validated HPLC-MS/MS method. PS and PG exposures were higher than that of APAP, while NAPQI concentrations were constantly below the detection limit of the analytical method. IV propacetamol administration produced 30% more APAP than oral administration. However, propacetamol released a significantly lower amount of active moiety in dogs than in humans. The propacetamol dose administered in this study did not produce plasma APAP concentrations above the threshold sufficient to provide analgesia in adult humans (4 μg/mL). In conclusion, direct IV injection of APAP instead of propacetamol might be a better clinical option for pain relief in dogs., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Metabolites present in human urine can be influenced by individual physiological parameters (e.g., body mass index [BMI], age, and sex). Observation of altered metabolites concentrations could provide insight into underlying disease pathology, disease prognosis and diagnosis, and facilitate discovery of novel biomarkers., Methods: Quantitative metabolomics analysis in the urine of 183 healthy individuals was performed based on high-resolution liquid chromatography-mass spectrometry (LC-MS). Coefficients of variation were obtained for 109 urine metabolites of all the 183 human healthy subjects., Results: Three urine metabolites (such as dehydroepiandrosterone sulfate, acetaminophen glucuronide, and p-anisic acid) with CV 183  > 0.3, for which metabolomics studies have been scarce, are considered highly variable here. We identified 30 age-related metabolites, 18 BMI-related metabolites, and 42 sex-related metabolites. Among the identified metabolites, three metabolites were found to be associated with all three physiological parameters (age, BMI, and sex), which included dehydroepiandrosterone sulfate, 3-methylcrotonylglycine and N-acetyl-aspartic acid. Pearson's coefficients demonstrated that some age-, BMI-, and sex-related compounds are strongly correlated, suggesting that age, BMI, and sex could affect them concomitantly., Conclusion: Metabolic differences between distinct physiological statuses were found to be related to several metabolic pathways (such as the caffeine metabolism, the amino acid metabolism, and the carbohydrate metabolism), and these findings may be key for the discovery of new diagnostics and treatments as well as new understandings on the mechanisms of some related diseases., (© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Background: Extensive efforts have been made toward reducing postoperative opioid use in children. In this study, we assessed whether propacetamol, or a nonsteroidal anti-inflammatory drug (NSAID), or their combination could effectively reduce opioid use in children after laparoscopic inguinal hernia repair., Methods: This randomized, double-blind clinical trial included 159 children aged 6 months to 6 years. Children were allocated into 1 of the following 3 groups: group I was treated with 10 mg·kg-1 ibuprofen, group P was treated with 30 mg·kg-1 propacetamol, and group I + P was treated with both drugs in their respective concentrations. If the face-legs-activity-crying-consolability (FLACC) score was ≥4 during the postanesthesia care unit stay, 1.0 µg·kg-1 fentanyl was administered as a rescue analgesic. The number of patients who received rescue fentanyl in the postanesthesia care unit was defined as the primary outcome; this was analyzed using the χ2 test. The secondary outcomes included the FLACC and the parents' postoperative pain measure (PPPM) scores until the 24-hour postoperative period., Results: Among the 144 enrolled patients, 28.6% in group I, 66.7% in group P, and 12.8% in group I + P received rescue fentanyl in the postanesthesia care unit (P < .001). The highest FLACC score was lower in group I + P than in either group I or P (P = .007 and P < .001, respectively). Group I + P presented significantly lower PPPM scores than group P at 4 and 12 hours postoperative (P = .03 and .01, respectively)., Conclusions: The use of ibuprofen plus propacetamol immediately following laparoscopic hernia repair surgery in children resulted in the reduced use of an opioid drug compared with the use of propacetamol alone., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 International Anesthesia Research Society.)

Background: Acetaminophen (APAP) is a widely self-prescribed analgesic for mild to moderate pain, but overdose or repeat doses can lead to liver injury and death. Kalyra Pharmaceuticals has developed a novel APAP analog, KP-1199, currently in Phase 1 clinical studies, which lacks hepatotoxicity. In this study, the authors evaluated the antinociceptive effect of KP-1199 on thermal injury-induced nociceptive behaviors as well as hemostatic parameters using human blood samples., Methods: Full-thickness thermal injury was induced in anesthetized adult male Sprague-Dawley rats. On day 7 post-injury, KP-1199 (30 and 60 mg/kg) or APAP (60 mg/kg) was administered orally. Antinociception of KP-1199 and APAP were assessed at multiple time points using Hargreaves' test. In separate experiments, human whole blood was collected and treated with either KP-1199, APAP, or Vehicle (citrate buffer) at 1× (214 μg/ml) and 10× (2140 μg/ml) concentrations. The treated blood samples were assessed for: clotting function, thrombin generation, and platelet activation., Results: APAP did not produce antinociceptive activity. KP-1199 treatment significantly increased the nociceptive threshold, and the antinociceptive activity persisted up to 3 h post-treatment. In human samples, 10× APAP caused significantly prolonged clotting times and increased platelet activation, whereas KP-1199 had caused no negative effects on either parameter tested., Conclusion: These results suggest that KP-1199 possesses antinociceptive activity in a rat model of thermal injury. Since KP-1199 does not induce platelet activation or inhibit coagulation, it presents an attractive alternative to APAP for analgesia, especially for battlefield or surgical scenarios where blood loss and blood clotting are of concern., (© 2021 AABB. his article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Treating neuropathic pain remains challenging, and therefore new pharmacological strategies are urgently required. Here, the enhancement of glycinergic neurotransmission by either facilitating glycine receptors (GlyR) or inhibiting glycine transporter (GlyT) function to increase extracellular glycine concentration appears promising. Propacetamol is a N , N -diethylester of acetaminophen, a non-opioid analgesic used to treat mild pain conditions. In vivo, it is hydrolysed into N , N -diethylglycine (DEG) and acetaminophen. DEG has structural similarities to known alternative GlyT1 substrates. In this study, we analyzed possible effects of propacetamol, or its metabolite N , N -diethylglycine (DEG), on GlyRs or GlyTs function by using a two-electrode voltage clamp approach in Xenopus laevis oocytes. Our data demonstrate that, although propacetamol or acetaminophen had no effect on the function of the analysed glycine-responsive proteins, the propacetamol metabolite DEG acted as a low-affine substrate for both GlyT1 (EC50 > 7.6 mM) and GlyT2 (EC50 > 5.2 mM). It also acted as a mild positive allosteric modulator of GlyRα1 function at intermediate concentrations. Taken together, our data show that DEG influences both glycine transporter and receptor function, and therefore could facilitate glycinergic neurotransmission in a multimodal manner.

Acetaminophen (APAP), a widely used analgesic-antipyretic drug, is frequently detected in the environment and may pose ecological risks to aquatic communities. In this work, an APAP-degrading organism, designated as Ensifer sp. POKHU, was isolated from activated sludge (AS) enriched with APAP. POKHU degraded up to 630 mg/L of APAP without substrate inhibition. The bacterium metabolized APAP to hydroquinone (HQ) via 4-aminophenol (4-AP). APAP derivatives, 4AP, HQ, and 1,4-benzoquinone (BQ), frequently detected in the environment, were found to inhibit nitrogen metabolism (ammonium oxidation) to a greater extent than APAP. POKHU had the ability to degrade varying levels (0.4-40 mg/L) of 4-AP, HQ, and BQ, which indicated a great potential for detoxification in environments contaminated with both APAP and its derivatives. The addition of POKHU to fresh AS samples taken from a wastewater treatment plant greatly increased the biotransformation rates of APAP from 5.6 d -1 (no POKHU augmentation) to >20.0 d -1 (5% POKHU). Bioaugmentation with POKHU reduced 400 μg/L of APAP to levels below its ecotoxicity threshold within 4 h, which is shorter than the typical hydraulic retention times for full-scale AS processing. Overall, this study identified a new auxiliary biological agent for APAP detoxification, which could degrade both APAP and its metabolic derivatives (those that can be more toxic than the parent contaminant, APAP). The results have practical implications for developing a biological means (detoxification and bioaugmentation) of treating high-strength pharmaceutical waste streams, such as wastewater from hospitals and drug manufactures, and of landfill leachates., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Paracetamol (acetaminophen, APAP) is the most frequently used analgesic drug worldwide. However, patients in several specific populations can have an increased exposure to toxic APAP metabolites. Therefore, APAP-protein adducts have been proposed as an alternative marker for the assessment of APAP intoxications and as an effective tool to study and steer APAP treatment in patients with an increased risk of APAP-induced liver damage. These adducts have been determined in plasma or serum as a matrix. Blood microsampling allows the determination of a variety of analytes, including protein adducts, in a drop of blood, facilitating convenient follow-up of patients in a home-sampling context, as well as repeated sampling of pediatric patients. We therefore evaluated the use of blood-based volumetric microsamples for the quantification of APAP-protein adducts. Quantitative methods for the determination of APAP-protein adducts in dried blood and dried plasma volumetric absorptive microsamples were developed and validated. Also a preliminary evaluation of pediatric patient dried blood microsamples was conducted. Method validation encompassed the evaluation of selectivity, carry over, calibration model, accuracy and precision, matrix effect, recovery and the effect of the hematocrit on the recovery, dilution integrity, and stability. All pre-set acceptance criteria were met, except for stability. Spiking of blank blood with APAP revealed a concentration-dependent ex vivo formation of APAP-protein adducts, resulting in a response for the measurand APAP-Cys, with an apparent role for the red blood cell fraction. Analysis of authentic samples, following intake of APAP at therapeutic dosing, revealed much higher APAP-Cys concentrations in dried blood vs. dried plasma samples, making interpretation of the results in the context of published intervals difficult. In addition, in contrast to what was observed during method validation, the data obtained for the patient samples showed a high and unacceptable variation. We conclude that, for a combination of reasons, dried blood is not a suitable matrix for the quantification of APAP-protein adducts via the measurement of the APAP-Cys digestion product. The collection of plasma or serum, either in the form of a liquid sample or a dried microsample for this purpose is advised., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Postoperative opioid analgesia may cause respiratory depression. We assessed whether following total hip arthroplasty, placebo-adjusted reductions in morphine consumption at 48 hours with parecoxib (47.0%), propacetamol (35.1%) or parecoxib plus propacetamol (67.9%) translated into a reduction in hypoxemic events., Methods: This was a post hoc analysis of a randomized, placebo-controlled, noninferiority study. Patients were randomly assigned to receive intravenous parecoxib (40 mg twice daily), propacetamol (2 g 4 times daily), parecoxib plus propacetamol (40 mg twice daily + 2 g 4 times daily) or placebo. Dose, date and time of morphine administration via patient-controlled analgesia were monitored throughout the study. In patients not receiving supplemental oxygen, peripheral blood oxygenation was assessed continuously for 48 hours after surgery. Hypoxemia was defined as peripheral oxygen saturation less than 90%. The times and oximeter readings of hypoxemic events were recorded. Pearson correlation coefficient was used to assess for correlations between cumulative morphine consumption at 48 hours and mean number of hypoxemic events., Results: A significantly smaller proportion of patients who received the combined treatment with parecoxib and propacetamol had hypoxemia versus placebo (2.8% v. 13.2%, p < 0.05), and the mean number of hypoxemic events was significantly smaller for parecoxib (0.12), propacetamol (0.06) and parecoxib plus propacetamol (0.03) versus placebo (0.36; all p < 0.05). There was no correlation between the reduction in cumulative morphine consumption at 48 hours and the mean number of hypoxemic events in any treatment group (all p > 0.1)., Conclusion: Following total hip arthroplasty, a greater than 70% reduction in morphine consumption may be necessary to translate into a corresponding reduction in hypoxemic events., Competing Interests: M. Essex, P. Salomon and S. Pan are employees of Pfizer and have stock or stock options with Pfizer. F. Camu has acted as consultant to pharmaceutical companies and health authorities, outside the submitted work. R. Cheung was an employee of Pfizer at the time of study conduct. No other competing interests were declared., (© 2020 Joule Inc. or its licensors.)

Importance: Prior studies have raised concern about maternal acetaminophen use during pregnancy and increased risk of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in their children; however, most studies have relied on maternal self-report., Objective: To examine the prospective associations between cord plasma acetaminophen metabolites and physician-diagnosed ADHD, ASD, both ADHD and ASD, and developmental disabilities (DDs) in childhood., Design, Setting, and Participants: This prospective cohort study analyzed 996 mother-infant dyads, a subset of the Boston Birth Cohort, who were enrolled at birth and followed up prospectively at the Boston Medical Center from October 1, 1998, to June 30, 2018., Exposures: Three cord acetaminophen metabolites (unchanged acetaminophen, acetaminophen glucuronide, and 3-[N-acetyl-l-cystein-S-yl]-acetaminophen) were measured in archived cord plasma samples collected at birth., Main Outcomes and Measures: Physician-diagnosed ADHD, ASD, and other DDs as documented in the child's medical records., Results: Of 996 participants (mean [SD] age, 9.8 [3.9] years; 548 [55.0%] male), the final sample included 257 children (25.8%) with ADHD only, 66 (6.6%) with ASD only, 42 (4.2%) with both ADHD and ASD, 304 (30.5%) with other DDs, and 327 (32.8%) who were neurotypical. Unchanged acetaminophen levels were detectable in all cord plasma samples. Compared with being in the first tertile, being in the second and third tertiles of cord acetaminophen burden was associated with higher odds of ADHD diagnosis (odds ratio [OR] for second tertile, 2.26; 95% CI, 1.40-3.69; OR for third tertile, 2.86; 95% CI, 1.77-4.67) and ASD diagnosis (OR for second tertile, 2.14; 95% CI, 0.93-5.13; OR for third tertile, 3.62; 95% CI, 1.62-8.60). Sensitivity analyses and subgroup analyses found consistent associations between acetaminophen buden and ADHD and acetaminophen burden and ASD across strata of potential confounders, including maternal indication, substance use, preterm birth, and child age and sex, for which point estimates for the ORs vary from 2.3 to 3.5 for ADHD and 1.6 to 4.1 for ASD., Conclusions and Relevance: Cord biomarkers of fetal exposure to acetaminophen were associated with significantly increased risk of childhood ADHD and ASD in a dose-response fashion. Our findings support previous studies regarding the association between prenatal and perinatal acetaminophen exposure and childhood neurodevelopmental risk and warrant additional investigations.

The aim of this paper is to develop a mild and efficient extraction method for polysaccharides from Sinonovacula constricta (SCP) using enzyme extraction, and analyze the structural characteristics and antioxidant activities of the two purified polysaccharide fractions (SCP-1 and SCP-2). Firstly, enzyme extraction conditions were optimized, and the conditions were found to be, as follows: enzymolysis time 173.0 min, pH 8.2, enzymolysis temperature 50.0 ℃ and enzyme content 4.0%. Comparison between enzymatic extraction and water extraction was obtained from visual, UV-visible and IR spectrum images. The results clearly indicate that there is no significant difference between them with regard to the composition of the SCP fraction, but the polysaccharide content produced by enzymatic extraction is higher. Then, the physicochemical properties and structural characteristics of SCP-1 and SCP-2 were investigated using FT-TR, UV, GC and HPGPC. The carbohydrate content, sulfuric radicals and uronic acids of the two fractions were detected. Both SCP-1 and SCP-2 were mainly consisted of glucose, but their molecular weights were different. In addition, compared the Fe 2+ chelating activity, ABTS + radical and superoxide radical scavenging activity, and lipid peroxidation inhibition activity of SCP-1 and SCP-2, it turned out that SCP-2 had stronger antioxidant activity than SCP-1., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The pharmacokinetics of some hepatically cleared drugs have been reported to fluctuate in patients with renal impairment, but the definitive factors have not been clarified. We compared the pharmacokinetics of some drugs with different hepatic elimination processes in a chronic kidney disease (CKD) rat model, to optimize their administration during kidney injury. We chose indocyanine green (ICG), midazolam (MDZ), and acetaminophen (APAP) as reference drugs to determine changes in hepatic clearance pathways in presence of CKD. Drugs were intravenously administered via the jugular vein to the CKD model rats, previously established by adenine administration, and then, blood, bile, and urine samples were collected. The plasma concentration of ICG, which is eliminated into the bile without biotransformation, increased; and its total body clearance (CL tot ) significantly decreased in the CKD group compared to the control group. Moreover, the plasma concentrations of MDZ and APAP, metabolized in the liver by CYP3A and Ugt1a6 enzymes, respectively, were higher in the CKD group than in the control group. The biliary clearances of APAP and its derivative APAP-glucuronide increased in the CKD group, whereas their renal clearances were markedly decreased with respect to those in the control group. Altogether, plasma concentrations of some hepatically eliminated drugs increased in the CKD rat model, but depending on their pharmacokinetic characteristics. This study provides useful information for optimizing the administration of some hepatically cleared drugs in CKD patients.

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., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Limited data exist regarding paracetamol metabolism after overdose in the neonate. We report a case of repeated supratherapeutic overdose in a neonate with paracetamol metabolite concentrations. Case report: A 10-day-old male neonate presented to hospital after repeated supratherapeutic dosing of paracetamol. Paracetamol concentration 19.5 h post-last dose was 381 μmol/L and 236 μmol/L, 9 h later. Initial alanine aminotransferase (ALT) was normal (18 IU/L) and total bilirubin was 262 μmol/L ( N  < 300). Acetylcysteine infusion was commenced and ceased 27 h later, when serum paracetamol was undetectable and alanine aminotransferase remained normal.Initial paracetamol elimination half-life was 14.5 h. Analysis of serum paracetamol metabolites showed paracetamol-glucuronide was the major metabolite on presentation (64%). After acetylcysteine was commenced, paracetamol concentration fell, serum bilirubin increased, and paracetamol-sulfate represented a larger proportion of total metabolites (72%). Notably, paracetamol cytochrome (CYP450), cysteine- and mercapturate-conjugates, represented 21% of total measured metabolites on presentation. Conclusion: Repeated supratherapeutic ingestion of paracetamol in the neonate was associated with prolonged elimination half-life. Of note, this was in the presence of unconjugated hyperbilirubinaemia. CYP450 metabolism of paracetamol did not appear to be reduced in this neonate when compared to paracetamol metabolite ratios in older age groups.

Zebrafish larvae are increasingly used for pharmacological research, but internal drug exposure is often not measured. Understanding pharmacokinetics is necessary for reliable translation of pharmacological results to higher vertebrates, including humans. Quantification of drug clearance and distribution requires measurements of blood concentrations. Additionally, measuring drug metabolites is of importance to understand clearance in this model organism mechanistically. We therefore mechanistically studied and quantified pharmacokinetics in zebrafish larvae, and compared this to higher vertebrates, using paracetamol (acetaminophen) as a paradigm compound. A method was developed to sample blood from zebrafish larvae 5 days post fertilization. Blood concentrations of paracetamol and its major metabolites, paracetamol-glucuronide and paracetamol-sulfate, were measured. Blood concentration data were combined with measured amounts in larval homogenates and excreted amounts and simultaneously analyzed through nonlinear mixed-effects modeling, quantifying absolute clearance and distribution volume. Blood sampling from zebrafish larvae was most successful from the posterior cardinal vein, with a median volume (interquartile range) of 1.12 nl (0.676-1.66 nl) per blood sample. Samples were pooled ( n = 15-35) to reach measurable levels. Paracetamol blood concentrations at steady state were only 10% of the external paracetamol concentration. Paracetamol-sulfate was the major metabolite, and its formation was quantified using a time-dependent metabolic formation rate. Absolute clearance and distribution volume correlated well with reported values in higher vertebrates, including humans. Based on blood concentrations and advanced data analysis, the mechanistic and quantitative understanding of paracetamol pharmacokinetics in zebrafish larvae has been established. This will improve the translational value of this vertebrate model organism in drug discovery and development. SIGNIFICANCE STATEMENT: In early phases of drug development, new compounds are increasingly screened in zebrafish larvae, but the internal drug exposure is often not taken into consideration. We developed innovative experimental and computational methods, including a blood-sampling technique, to measure the paradigm drug paracetamol (acetaminophen) and its major metabolites and quantify pharmacokinetics (absorption, distribution, elimination) in zebrafish larvae of 5 days post fertilization with a total volume of only 300 nl. These parameter values were scaled to higher vertebrates, including humans., (Copyright © 2019 by The Author(s).)

Acetaminophen (APAP)-induced liver injury is the main cause of acute liver failure. This study investigated the role of microsomal prostaglandin E synthase 2 (mPGES-2), discovered as one of the prostaglandin E2 (PGE2) synthases, in mediating APAP-induced liver injury. Using mPGES-2 wild-type (WT) and knockout (KO) mice, marked resistance to APAP-induced liver damage was found in mPGES-2 KO, as indicated by robust improvement of liver histology, changes in liver enzyme release, and marked decrease in APAP-cysteine adducts (APAP-CYS) and inflammatory markers. Moreover, the results confirmed that increase in liver PGE2 content in KO mice under basal conditions was not critical for the protection from APAP-induced liver injury. Importantly, mPGES-2 deletion inhibited the production of malondialdehyde (MDA), increasing glutathione (GSH) level. Enhanced GSH level may contribute to the inhibition of APAP toxicity in mPGES-2 KO mice. To further elucidate the role of mPGES-2 in the liver injury induced by APAP, adeno-associated viruses (AAV) were used to overexpress mPGES-2 in the liver. The results showed that mPGES-2 overexpression aggravates liver injury associated with an increase in inflammatory markers and chemokines after APAP treatment. Moreover, a lower level of GSH was detected in the mPGES-2 overexpression group compared to the control group. Collectively, our findings indicate that mPGES-2 plays a critical role in regulating APAP-induced liver injury, possibly by regulating GSH and APAP-CYS level, which may provide a potential therapeutic strategy for the prevention and treatment of APAP-induced liver injury.

Sulfotransferases are categorized as phase II metabolic enzymes. Human sulfotransferase 1A1 (SULT1A1) is involved in the sulfonation of xenobiotics with aid from the cofactor 3'-phosphoadenosine-5'-phosphosulfate that acts as a sulfonate donor. In this study, we have attempted to immobilize SULT1A1 on magnetic microparticles (MMs). Different functionalized MMs were used to immobilize SULT1A1 and their enzyme activity was compared to the control (enzyme in solution). Paracetamol was used as model substrate. Separation of paracetamol and paracetamol sulfate by CE-UV was optimized and validated. MMs with epoxy based immobilization of SULT1A1 showed better enzyme activity. Hence, they were tested for repeated usage to allow their implementation for the development of a CE immobilized micro enzyme reactor., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Orthocetamol is a regioisomer of the well-known pain medication paracetamol and a promising analgesic and an anti-arthritic medicament itself. However, orthocetamol cannot be grown as single crystals suitable for X-ray diffraction, so its crystal structure has remained a mystery for more than a century. Here, we report the ab-initio structure determination of orthocetamol obtained by 3D electron diffraction, combining a low-dose acquisition method and a dedicated single-electron detector for recording the diffracted intensities. The structure is monoclinic, with a pseudo-tetragonal cell that favors multiple twinning on a scale of a few tens of nanometers. The successful application of 3D electron diffraction to orthocetamol introduces a new gold standard of total structure solution in all cases where X-ray diffraction and electron-microscope imaging methods fail., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We investigated the potential hepatoprotective effect of Radix Bupleuri (RB) by inducing acute liver injury (ALI) in an animal model using acetaminophen (APAP) after pretreatment with RB aqueous extract for three consecutive days. Compared to those of the APAP group, the biochemical and histological results of the RB pretreatment group showed lower serumaspartate transaminase (AST) and alanine transaminase (ALT) levels as well as less liver damage. Pharmacokinetic study of the toxicity related marker acetaminophen-cysteine (APC) revealed a lower exposure level in rats, suggesting that RB alleviated APAP-induced liver damage by preventing glutathione (GSH) depletion. The results of cocktail approach showed significant inhibition of CYP2E1 and CYP3A activity. Further investigation revealed the increasing of CYP2E1 and CYP3A protein was significantly inhibited in pretreatment group, while no obvious effect on gene expression was found. Therefore, this study clearly demonstrates that RB exhibited significant protective action against APAP-induced acute live injury via pretreatment, and which is partly through inhibiting the increase of activity and translation of cytochrome P450 enzymes, rather than gene transcription., (Copyright © 2019 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

In Europe, 50-60% of pregnant women uses paracetamol (PCM), also known as acetaminophen. While it was considered to be safe, recent studies have shown an association between prenatal exposure to PCM and increased incidences of autism, cryptorchidism, asthma and ADHD. In this study the transplacental transfer of PCM and its metabolites was investigated using an ex vivo human placenta perfusion model (closed circuit; n = 38). Maternal-to-foetal (M-F) and foetal-to-maternal (F-M) transplacental transfer was determined at a concentration correlating with the maximum and steady state concentration in normal clinical use. Antipyrine (AP) was added as reference compound. Samples of the foetal and maternal perfusion medium were taken until 210 (PCM) or 360 min (paracetamol sulphate (PCM-S) and paracetamol glucuronide (PCM-G). PCM and AP concentrations reached an equilibrium between foetal and maternal compartments within the duration of the perfusion experiment and irrespective of the transfer direction. The percentage placental transfer of PCM was 45% (M-F and F-M). For PCM-S, transfer was 39% (M-F) and 28% (F-M), while the PCM-G transfer was 34% (M-F) and 25% (F-M). During placenta perfusions with the metabolites slight conversion (3.5-4.1%) to PCM was observed. In conclusion, PCM crosses the placental barrier rapidly via passive diffusion. Differences in flow rate and villous placental structure explain the significantly faster M-F transfer than F-M transfer of PCM. The larger and more hydrophilic molecules PCM-S and PCM-G cross the placenta at a significantly lower rate. Moreover, their F-M transport is about 40% slower than M-F transport, suggesting involvement of a transporter., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A series of nitrate ester analogues of the acetaminophen derivative SCP-1 were prepared by triflic acid catalyzed O-acylation of SCP-1 with chloroalkanoyl chlorides followed by nitration with silver nitrate. The chloroesters and corresponding nitrate esters were obtained in high yields. Preliminary hepatotoxicity studies revealed nitrate esters 5b (MD-38) and 5c (MD-39) to be well tolerated by human hepatocytes and had little effect on the three cytochrome P450 enzymes tested (CYP3A4, CYP2E1 and CYP2D6). In addition, the nitrate ester 5c (MD-39) exhibited antipyretic activity similar to acetaminophen., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A rapid, specific, and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed and validated to simultaneously quantify N-acetyl-p-benzoquinoneimine (NAPQI), acetaminophen-glutathione (acetaminophen-glut) and acetaminophen-glucuronide (acetaminophen-gluc) in mouse plasma, liver and kidney homogenates. Analytes were eluted by a binary gradient mobile phase composed of water (phase A) and methanol containing 0.1% formic acid (phase B) at a flow rate of 0.3 mL/min, which was performed on a CAPCELL PAK C 18 MG II column. It took 3.2 min to detect three analytes in a single run. Quantification was carried out in positive mode combined with multiple reaction monitoring. The validation of the LC-MS/MS method consisted of specificity, linearity, precision, accuracy, protein precipitation recovery, matrix effect, dilution integrity and stability. The plasma and tissue homogenate calibration curves were linear over concentration ranges of 0.050-5.00, 0.050-5.00 and 0.100-40.0 μg/mL, with a lower limit of quantification of 0.050, 0.050, and 0.100 μg/mL for NAPQI, acetaminophen-glut and acetaminophen-gluc, respectively. The intra- and inter-run precision values were within 12.47% for NAPQI, 12.11% for acetaminophen-glut and 11.86% for acetaminophen-gluc at their lower limit of quantitation levels. The samples were stable under all tested conditions. This method was successfully applied to study the pharmacokinetics of NAPQI, acetaminophen-glut and acetaminophen-gluc in ICR mice following oral administration of 200 mg/kg of acetaminophen suspension., (© 2018 John Wiley & Sons, Ltd.)

Tumor biomarkers are highly desirable for the screening of patients with a risk of tumor development and progression. Here, we report a beta-galactosidase (β-gal)-responsive acetaminophen (β-GR-APAP) as a synthetic plasma biomarker for targeted tumor detection. Tumor β-gal labeling via the recognition of tumor-related antigen enabled the detection of a tumor using β-GR-APAP.

Acetaminophen (APAP) is one of the most intensively studied compounds that causes hepatotoxicity in the pericentral region of the liver lobules. However, spatio-temporal information on the distribution of APAP, its metabolites and GSH adducts in the liver tissue is not yet available. Here, we addressed the question, whether APAP-GSH adducts and GSH depletion show a zonated pattern and whether the distribution of APAP and its glucuronide as well as sulfate conjugates in liver lobules are zonated. For this purpose, a matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) technique was established, where the MSI images were superimposed onto CYP2E1 immunostained tissue. A time-dependent analysis (5, 15, 30, 60, 120, 240, 480 min) after intraperitoneal administration of 300 mg/kg APAP and a dose-dependent analysis (56 up to 500 mg APAP/kg) at 30 min were performed. The results demonstrate that the MALDI MSI technique allows the assignment of compounds and their metabolites to specific lobular zones. APAP-GSH adducts and GSH depletion occurred predominantly in the CYP2E1-positive zone of the liver, although GSH also decreased in the periportal region. In contrast, the parent compound, APAP sulfate and APAP glucuronide did not show a zonated pattern and tissue concentrations showed a similar time course as the corresponding analyses were performed with blood from the portal and liver veins. In conclusion, the present study is in agreement with the concept that pericentral CYPs form NAPQI that in the same cell binds to and depletes GSH but a lower level of GSH adducts is also observed in the periportal region. The results also provide further evidence of the recently published concept of 'aggravated loss of clearance capacity' according to which also liver tissue that survives intoxication may transiently show decreased metabolic capacity.

Background: We aimed to compare the antipyretic efficacy, safety, and tolerability between oral dexibuprofen and intravenous propacetamol in children with upper respiratory tract infection (URTI) presenting with fever., Methods: Patients aging from 6 months to 14 years admitted for URTI with axillary body temperature ≥ 38.0 °C were enrolled and randomized into the study or control group. Patients in the study group were intravenously infused with propacetamol and subsequently oral placebo medication was administered. Patients in the control group were intravenously infused with 100 mL of 0.9% sodium chloride solution without propacetamol and then oral dexibuprofen was administered. We checked the body temperature of all patients at 0.5 h (hr), 1 h, 1.5 h, 2 h, 3 h, 4 h, and 6 h after oral placebo or dexibuprofen had been applied., Results: A total of 263 patients (125 in the study group) were finally enrolled. The body temperatures of patients in the study group were significantly lower until 2 h after administration (37.73 ± 0.58 vs 38.36 ± 0.69 °C (p < 0.001), 37.37 ± 0.53 vs 37.88 ± 0.69 °C (p < 0.001), 37.27 ± 0.60 vs 37.62 ± 0.66 °C (p < 0.001), 37.25 ± 0.62 vs 37.40 ± 0.60 °C (p = 0.0452), at 0.5 h, 1 h, 1.5 h, and 2 h, respectively). The two groups showed no significant differences in terms of the range of body temperature decrease, the Area Under the Curve of body temperature change for antipyretic administration-and-time relationship, the maximum value of body temperature decrease during the 6 h test period, the number of patients whose body temperature normalized (< 37.0 °C), the mean time when first normalization of body temperature, and the development of adverse events including gastrointestinal problem, elevated liver enzyme, and thrombocytopenia., Conclusions: Intravenous propacetamol may be a safe and effective choice for pediatric URTI patients presenting with fever who are not able to take oral medications or need faster fever control., Trial Registration: CRIS KCT0002888 . Date of registration: July 31st, 2013.

Acetaminophen (APAP) overdose can induce acute liver injury (ALI) with significant morbidity and mortality. Propacetamol is an APAP prodrug, which is clinically bioequivalent to APAP. Kaempferol, a dietary flavonoid, has antioxidant, anti-inflammatory, and anti-apoptotic effects. In this study, we investigated the protective effect of kaempferol on propacetamol-induced ALI and its underlying mechanism in mice. Kaempferol pretreatment (125 mg/kg) before propacetamol injection significantly decreased propacetamol-induced serum ALT and AST activities, and DNA fragmentation. Kaempferol administration also reduced propacetamol-induced oxidative stress by inhibiting thiobarbituric acid reactive substances (TBARS) and 3-nitrotyrosine (3-NT) formation partly through downregulation of cytochrome P450 2E1 (CYP2E1) expression, upregulation of UDP glucuronosyltransferase family 1 member A1 (UGT1A1) expression, restoration of the activities of antioxidant enzymes including SOD, GPx and catalase toward normal, recovery of propacetamol-suppressed Nrf2 and GCLC expressions, and maintenance of normal glutathione level. Furthermore, kaempferol markedly attenuated APAP-induced serum TNF-α and IL-6 productions, downregulated APAP-induced phosphorylations of JNK and ERK, and decreased early hepatic apoptosis via decreasing Bax/Bcl-2 ratio and caspase 3 activation. Furthermore, administration of N-acetylcysteine (NAC) and kaempferol significantly rescued more mice than a low dose of NAC only did when a lethal dose of propacetamol injected and therapized at a delayed time point. These data suggested that kaempferol protects the liver against propacetamol-induced injury through anti-oxidative, anti-inflammatory and anti-apoptotic activities., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Anesthetic care for termination of atrial fibrillation with catheter ablation poses significant challenges due to significant pain and lengthy procedure. A delicate polypharmacy combining anesthetic agents to minimize respiratory depression and hemodynamic changes and to provide satisfactory sedation and analgesia is needed., Methods: Ninety-eight patients were randomized into two groups receiving either two grams of propacetamol or normal saline intravenously for 20 minutes before anesthesia. Monitored anesthesia care was provided with midazolam and remifentanil., Results: Total amounts of remifentanil infused were similar between the groups (626±251 vs. 597±315 μg, P=0.606). Accounting for the mean duration of the procedure and the elimination half-life of propacetamol, remifentanil requirements were significantly less among patients whose procedure ended within 180 minutes (N.=56) in the propacetamol group than those in the control group (540±194 vs. 421±164 μg, P=0.017). In the control group, the incidence of analgesics usage 24 hours after the procedure was significantly greater (43% vs. 23%, P=0.038), and patients exhibited a higher pain score (3.1±2.1 vs. 1.9±2.1, P=0.007), compared to the propacetamol group., Conclusions: The addition of a single dose of pre-emptive propacetamol showed promising results in terms of opioid consumption in patients whose procedure ended within 180 minutes. It provided better post-procedural pain control, compared with midazolam plus remifentanil alone.

Objectives: Clinical studies have indicated that transient hypotension can occur after propacetamol administration. This study aimed to analyze the hemodynamic changes after propacetamol administration in patients visiting the ED due to febrile UTI. We also examined the incidence of propacetamol-induced hypotension and compared the clinical characteristics of patients with persistent hypotension, defined as requiring additional fluids or vasopressors, to those with transient hypotension., Methods: A retrospective analysis of the electronic medical records of patients who visited the ED between June 2015 and May 2016, were diagnosed with febrile UTI, and treated with propacetamol, was conducted., Results: We included 195 patients in this study; of these, 87 (44.6%) showed hypotension. In all patients, significant decreases in systolic blood pressure (SBP; 135.06±20.45mmHg vs 117.70±16.41mmHg), diastolic blood pressure (DBP; 79.74±12.17mmHg vs 69.69±10.96mmHg), and heart rate (97.46±17.14mmHg vs 90.72±14.90mmHg) were observed after propacetamol administration. The basal SBP and DBP were higher in the hypotension than in the non-hypotension group (basal SBP: 144.4±22.3mmHg vs 127.6±15.3mmHg; basal DBP: 83.3±12.6mmHg vs 76.9±11.0mmHg). Patients with persistent hypotension had a lower baseline BP, which was not elevated despite fever, and a higher rate of bacteremia than those with transient hypotension., Conclusions: Although febrile UTI patients treated with propacetamol in the ED showed hemodynamic changes, these changes did not have a large effect on their prognosis. However, in patients who showed bacteremia or a normal initial BP despite fever, the possibility of developing persistent hypotension should be considered., (Copyright © 2017. Published by Elsevier Inc.)

Post-translational protein modification by addition or removal of the small polypeptide ubiquitin is involved in a range of critical cellular processes, like proteasomal protein degradation, DNA repair, gene expression, internalization of membrane proteins, and drug sensitivity. We recently identified genes important for acetaminophen (APAP) toxicity in a comprehensive screen and our findings suggested that a small set of yeast strains carrying deletions of ubiquitin-related genes can be informative for drug toxicity profiling. In yeast, approximately 20 different deubiquitinating enzymes (DUBs) have been identified, of which only one is essential for viability. We investigated whether the toxicity profile of DUB deletion yeast strains would be informative about the toxicological mode of action of APAP. A set of DUB deletion strains was tested for sensitivity and resistance to a diverse series of compounds, including APAP, quinine, ibuprofen, rapamycin, cycloheximide, cadmium, peroxide and amino acids and a cluster analysis was performed. Most DUB deletion strains showed an altered growth pattern when exposed to these compounds by being either more sensitive or more resistant than WT. Toxicity profiling of the DUB strains revealed a remarkable overlap between the amino acid tyrosine and acetaminophen (APAP), but not its stereoisomer AMAP. Furthermore, co-exposure of cells to both APAP and tyrosine showed an enhancement of the cellular growth inhibition, suggesting that APAP and tyrosine have a similar mode of action., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Recently, there has been an emerging clinical data suggesting that intravenous propacetamol may cause iatrogenic hypotension. The primary objective of this study was to evaluate hemodynamic changes after propacetamol infusion in the emergency department (ED) with the patients of influenza A. Secondary objective was to assess the incidence of propacetamol-induced significant hypotension and to evaluate factors associated with this adverse effect by comparing two groups of patients with or without a significant reduction in blood pressure (BP)., Methods: We retrospectively reviewed the medical records of the patients with laboratory-confirmed influenza A who received intravenous propacetamol for the control of fever in the ED during the 2015-16 influenza season., Results: 101 patients of influenza A were included in this study. Overall, all the vital signs including BP, pulse rate and body temperature recorded after propacetamol administration were lower than the pre-infusion values. A significant reduction in BP was observed in 30 (29.7%) patients and 6 (20%) of them required crystalloid infusion. Interestingly, pre-infusion BPs were higher in the group of propacetamol-induced significant hypotension, yet there was no difference in post-infusion BPs between the groups., Discussion: To our knowledge this is the first study on the effect of intravenous propacetamol in the ED patients with influenza A infection. We hypothesized that the group with a significant reduction in BP could have higher sympathetic tone, consequently showing higher pre-infusion BPs and pulse rate. And there was no difference in post-infusion BPs because baroreflex homeostasis could compensate further decrease in BPs., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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., (Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.)

Competing Interests: Competing interests: None declared.

Several chemical routes related to the toxicity of paracetamol (APAP, also known as acetaminophen), its analogue N-acetyl-m-aminophenol (AMAP), and their deacetylated derivatives, were investigated using the density functional theory. It was found that AMAP is more resilient to chemical oxidation than APAP. The chemical degradation of AMAP into radical intermediates is predicted to be significant only when it is induced by strong oxidants. This might explain the apparent contradictions among experimental evidence regarding AMAP toxicity. All of the investigated species are incapable of oxidizing DNA, but they can damage lipids by H atom transfer (HAT) from the bis-allylic site, with the phenoxyl radical of AMAP being the most threatening to the lipids' chemical integrity. Regarding protein damage, Cys residues were identified as the most likely targets. The damage in this case may involve two different routes: (i) HAT from the thiol site by phenoxyl radicals and (ii) protein arylation by the quinone imine (QI) derivatives. Both are not only thermochemically viable, but also are very fast reactions. According to the mechanism identified here as the most likely one for protein arylation, a rather large concentration of QI would be necessary for this damage to be significant. This might explain why APAP is nontoxic in therapeutic doses, while overdoses can result in hepatic toxicity. In addition, the QI derived from both APAP and AMAP were found to be capable of inflicting this kind of damage. In addition, it is proposed that they might increase • OH production via the Fenton reaction, which would contribute to their toxicity.

1. Topical anesthesia with benzocaine or lidocaine occasionally causes methemoglobinemia, an uncommon but potentially fatal disorder where the blood has a reduced ability to transport oxygen. Previous in vitro studies using human whole blood have shown that benzocaine causes more methemoglobin (MetHb) formation than lidocaine, and that both compounds require metabolic transformation to form the MetHb producing species. In the current investigation, the active species of benzocaine forming the MetHb was investigated. 2. HPLC analysis of benzocaine samples incubated with human hepatic S9 showed the formation of a peak with the same UV spectrum and retention time as benzocaine hydroxylamine (BenzNOH). To confirm the activity of BenzNOH, MetHb production following exposure to the compound was determined in whole human blood using an Avoximeter 4000 CO-oximeter. 3. BenzNOH produced MetHb in a concentration dependent manner without the need for metabolic activation. Benzocaine in the presence of metabolic activation required a concentration of 500 μM to produce a similar degree of MetHb formation as 20 μM BenzNOH without activation. Previous work suggested that two metabolites of lidocaine may also form MetHb; N-hydroxyxylidine and 4-hydroxyxylidine. Of these two metabolites 4-hydroxyxylidine produced the most MetHb in whole blood in vitro in the absence of metabolic activation, however BenzNOH produced up to 14.2 times more MetHb than 4-hydroxyxylidine at a similar concentration. 4. These results suggest that the ability of benzocaine to form MetHb is likely to be mediated through its hydroxylamine metabolite and that this metabolite is inherently more active than the potentially MetHb-forming metabolites of lidocaine.

Background: Erlotinib is a tyrosine kinase inhibitor available for the treatment of non-small cell lung cancer. Paracetamol is an analgesic agent, commonly used in cancer patients. Because these drugs are often co-administered, there is an increasing issue of interaction between them., Objective: The aim of the study was to investigate the effect of paracetamol on the pharmacokinetic parameters of erlotinib, as well as the influence of erlotinib on the pharmacokinetics of paracetamol., Methods: The rabbits were divided into three groups: the rabbits receiving erlotinib (I ER ), the group receiving paracetamol (II PR ), and the rabbits receiving erlotinib+paracetamol (III ER+PR ). A single dose of erlotinib was administered orally (25mg) and was administered intravenously (35mg/kg). Plasma concentrations of erlotinib, its metabolite (OSI420), paracetamol and its metabolites - glucuronide and sulphate were measured with the validated method., Results: During paracetamol co-administration we observed increased erlotinib maximum concentration (C max ) and area under the plasma concentration-time curve from time zero to infinity (AUC 0-∞ ) by 87.7% and 31.1%, respectively. In turn, erlotinib lead to decreased paracetamol AUC 0-∞ by 35.5% and C max by 18.9%. The mean values of paracetamol glucuronide/paracetamol ratios for C max were 32.2% higher, whereas paracetamol sulphate/paracetamol ratios for C max and AUC 0-∞ were 37.1% and 57.1% lower in the II PR group, when compared to the III ER+PR group., Conclusions: Paracetamol had significant effect on the enhanced plasma exposure of erlotinib. Additionally, erlotinib contributed to the lower concentrations of paracetamol. Decreased glucuronidation and increased sulphation of paracetamol after co-administration of erlotinib were also observed., (Copyright © 2017. Published by Elsevier B.V.)

Background: 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., Methods: 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., Results: 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., Conclusions: 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.

Purpose: Researchers recently suggested intravenous paracetamol as a potential cause of hypotension. We aimed to investigate risk factors of paracetamol- and propacetamol-associated adverse drug reactions (ADRs) in Korean individuals., Methods: All adverse hypotension cases, regardless of suspected drug, and all ADRs associated with paracetamol and propacetamol use were collected from the Korea Adverse Event Reporting System database between 2011 and 2014. The seriousness, causality, and type of ADR were classified., Results: Of 4,771 cases of adverse hypotension, 403 (8.4%) were reported to be related to propacetamol. This was comparable to the rate of hypotension associated with fentanyl (454, 9.5%), the major suspected drug of hypotension. Paracetamol-associated hypotension accounted for merely 1.2% (55 cases) of all hypotension cases. Among ADRs associated with propacetamol use, hypotension was the most common (37.1%), whereas cutaneous reactions were the primary paracetamol-associated ADR. Propacetamol/paracetamol-associated hypotension was frequently recorded in older patients (≥54 years) (53.9 ± 25.8 vs. 42.8 ± 21.7, P < 0.001) and taking more concomitant drugs (1.9 ± 5.0 vs. 1.1 ± 3.2, P < 0.001). Also, compared with other ADRs associated by propacetamol/paracetamol, hypotension was more commonly assessed as a serious outcome (27.3% vs. 11.4%, P < 0.001). Regarding concomitant medications, the risk for hypotension associated with propacetamol was significantly increased in patients simultaneously taking antibacterials (J01), cold preparations (R05), drugs for acid related disorders (A02), blood substitutes (B05), or antithrombotics (B01)., Conclusions: Propacetamol was found to be a major suspected drug of pharmacologically associated hypotension in Korea. Older and male patients taking medications in combination with propacetamol/paracetamol should undergo monitoring of their blood pressure. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

Background: This study assessed non-inferiority of parecoxib vs. combination parecoxib+propacetamol and compared the opioid-sparing effects of parecoxib, propacetamol, and parecoxib+propacetamol vs. placebo after total hip arthroplasty., Methods: In this randomized, placebo-controlled, parallel-group, non-inferiority study, patients received one of four IV treatments after surgery: parecoxib 40 mg bid (n = 72); propacetamol 2 g qid (n = 71); parecoxib 40 mg bid plus propacetamol 2 g qid (n = 72); or placebo (n = 38) with supplemental IV patient-controlled analgesia (morphine). Patients and investigators were blinded to treatment. Pain intensity at rest and with movement was assessed regularly, together with functional recovery (modified Brief Pain Inventory-Short Form) and opioid-related side effects (Opioid-Related Symptom Distress Scale) questionnaires up to 48 h., Results: After 24 h, cumulative morphine consumption was reduced by 59.8% (P < 0.001), 38.9% (P < 0.001), and 26.8% (P = 0.005) in the parecoxib+propacetamol, parecoxib, and propacetamol groups, respectively, compared with placebo. Parecoxib did not meet criteria for non-inferiority to parecoxib+propacetamol. Parecoxib+propacetamol and parecoxib significantly reduced least-squares mean pain intensity scores at rest and with movement compared with propacetamol (P < 0.05). One day after surgery, parecoxib+propacetamol significantly reduced opioid-related symptom distress and decreased pain interference with function compared with propacetamol or placebo., Conclusion: Parecoxib and parecoxib+propacetamol provided significant opioid-sparing efficacy compared with placebo; non-inferiority of parecoxib to parecoxib+propacetamol was not demonstrated. Opioid-sparing efficacy was accompanied by significant reductions in pain intensity on movement, improved functional outcome, and less opioid-related symptom distress. Study medications were well tolerated., (© 2016 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

The leading cause of drug-induced liver injury in the developed world is overdose with N-acetyl-p-aminophenol (APAP). A comparative metabonomic approach was applied to the study of both xenobiotic and endogenous metabolic profiles reflective of in vivo exposure to APAP (300 mg/kg) and its structural isomer N-acetyl-m-aminophenol (AMAP; 300 mg/kg) in C57BL/6J mice, which was anchored with histopathology. Liver and urine samples were collected at 1 h, 3 h and 6 h post-treatment and analyzed by 1 H nuclear magnetic resonance (NMR) spectroscopy and gas chromatography-mass spectrometry (liver only). Histopathology revealed the presence of centrilobular necrosis from 3 h post-APAP treatment, while an AMAP-mediated necrotic endpoint was not observed within the timescale of this study, yet two of five treated mice showed minimal centrilobular eosinophilia. The 1 H-NMR xenobiotic metabolic profile of APAP-treated animals comprised of mercapturate (urine and liver) and glutathionyl (liver) conjugates detected at 1 h post-treatment. This finding corroborated the hepatic endogenous metabolic profile which showed depletion of glutathione from 1 h onwards. In contrast, AMAP glutathionyl conjugates were not detected, nor was AMAP-induced depletion of hepatic glutathione observed. APAP administration induced significant endogenous hepatic metabolic perturbations, primarily linked to oxidative and energetic stress, and perturbation of amino acid metabolism. Early depletion of glutathione was followed by depletion of additional sulfur-containing metabolites, while altered levels of mitochondrial and glycolytic metabolites indicated a disruption of energy homeostasis. In contrast, AMAP administration caused minimal, transient, distinct metabolic perturbations and by 6 h the metabolic profiles of AMAP-treated mice were indistinguishable from those of controls., Competing Interests: The authors declare that there is no conflict of interest.

Objectives: This study aimed to model the population pharmacokinetics of intravenous paracetamol and its major metabolites in neonates and to identify influential patient characteristics, especially those affecting the formation clearance (CL formation ) of oxidative pathway metabolites., Methods: Neonates with a clinical indication for intravenous analgesia received five 15-mg/kg doses of paracetamol at 12-h intervals (<28 weeks' gestation) or seven 15-mg/kg doses at 8-h intervals (≥28 weeks' gestation). Plasma and urine were sampled throughout the 72-h study period. Concentration-time data for paracetamol, paracetamol-glucuronide, paracetamol-sulfate, and the combined oxidative pathway metabolites (paracetamol-cysteine and paracetamol-N-acetylcysteine) were simultaneously modeled in NONMEM 7.2., Results: The model incorporated 259 plasma and 350 urine samples from 35 neonates with a mean gestational age of 33.6 weeks (standard deviation 6.6). CL formation for all metabolites increased with weight; CL formation for glucuronidation and oxidation also increased with postnatal age. At the mean weight (2.3 kg) and postnatal age (7.5 days), CL formation estimates (bootstrap 95% confidence interval; between-subject variability) were 0.049 L/h (0.038-0.062; 62 %) for glucuronidation, 0.21 L/h (0.17-0.24; 33 %) for sulfation, and 0.058 L/h (0.044-0.078; 72 %) for oxidation. Expression of individual oxidation CL formation as a fraction of total individual paracetamol clearance showed that, on average, fractional oxidation CL formation increased <15 % when plotted against weight or postnatal age., Conclusions: The parent-metabolite model successfully characterized the pharmacokinetics of intravenous paracetamol and its metabolites in neonates. Maturational changes in the fraction of paracetamol undergoing oxidation were small relative to between-subject variability.

Background: This randomized trial evaluated the effect of intravenous patient-controlled analgesia (IV-PCA) based on fentanyl mixed with either propacetamol or an equivalent volume of normal saline on postoperative nausea and vomiting (PONV) in highly susceptible patients undergoing spinal surgery., Materials and Methods: One hundred eight nonsmoking female patients were randomly and evenly allocated to receive IV-PCA with either propacetamol (4 g) or normal saline mixed to fentanyl (20 μg/kg). Primary study outcome was PONV incidence at 24 hours postsurgery. Secondary outcomes were nausea severity, pain intensity (100-mm visual analog scale), use of rescue antiemetics and analgesics, patient satisfaction, and adverse events at 6, 12, and 24 hours postsurgery., Results: Postsurgery, the propacetamol versus normal saline group had lower PONV incidence at 24 hours (41% vs. 66%, P=0.011); pain intensity at rest and rescue analgesic requirements at 6 to 12 hours (30±15 vs. 41±19, P=0.008; and 25% vs. 49%, P=0.036, respectively) and at 12 to 24 hours (25±15 vs. 35±17, P=0.008; and 19% vs. 42%, P=0.044, respectively); and higher patient satisfaction score (6.4±1.4 vs. 5.7±1.8, P=0.028)., Conclusions: In patients undergoing spinal surgery and at risk of developing PONV, continuous IV-PCA based on propacetamol mixed to fentanyl, relative to fentanyl alone, effectively reduced the incidence of PONV, pain intensity at rest, and additional use of rescue analgesics with higher patient satisfaction.

Propacetamol (PPCM) is a prodrug of paracetamol (PCM), which was generated to increase water solubility of PCM for intravenous delivery. PPCM is rapidly hydrolyzed by plasma esterases to PCM and diethylglycine and shares some structural and metabolic properties with lidocaine. Although PPCM is considered to be comparable to PCM regarding its analgesic properties, injection pain is a common side effect described for PPCM but not PCM. Injection pain is a frequent and unpleasant side effect of numerous drugs in clinical use, and previous reports have indicated that the ligand gated ion channels transient receptor potential ankyrin 1 (TRPA1) and transient receptor potential vanilloid 1 (TRPV1) can mediate this effect on sensory neurons. This study aimed to investigate molecular mechanisms by which PPCM, in contrast to PCM, causes injection pain. Therefore, human TRPV1 and TRPA1 receptors were expressed in human embryonic kidney 293 cells and investigated by means of whole-cell patch clamp and ratiometric calcium imaging. PPCM (but not PCM) activated TRPV1, sensitized heat-induced currents, and caused an increase in intracellular calcium. In TRPA1-expressing cells however, both PPCM and PCM evoked calcium responses but failed to induce inward currents. Intracutaneous injection of PPCM, but not of PCM, in human volunteers induced an intense and short-lasting pain and an increase in superficial blood flow, indicating activation of nociceptive C fibers and subsequent neuropeptide release. In conclusion, activation of human TRPV1 by PPCM seems to be a relevant mechanism for induction of pain upon intracutaneous injection and thus also for pain reported as an adverse side effect upon intravenous administration., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)

Introduction: Acetaminophen (paracetamol) is mainly metabolized via glucuronidation and sulphation, while the minor pathway through cytochrome P450 (CYP) 2E1 is held responsible for hepatotoxicity. In obese patients, CYP2E1 activity is reported to be induced, thereby potentially worsening the safety profile of acetaminophen. The aim of this study was to determine the pharmacokinetics of acetaminophen and its metabolites (glucuronide, sulphate, cysteine and mercapturate) in morbidly obese and non-obese patients., Methods: Twenty morbidly obese patients (with a median total body weight [TBW] of 140.1 kg [range 106-193.1 kg] and body mass index [BMI] of 45.1 kg/m(2) [40-55.2 kg/m(2)]) and eight non-obese patients (with a TBW of 69.4 kg [53.4-91.7] and BMI of 21.8 kg/m(2) [19.4-27.4]) received 2 g of intravenous acetaminophen. Fifteen blood samples were collected per patient. Population pharmacokinetic modelling was performed using NONMEM., Results: In morbidly obese patients, the median area under the plasma concentration-time curve from 0 to 8 h (AUC0-8h) of acetaminophen was significantly smaller (P = 0.009), while the AUC0-8h ratios of the glucuronide, sulphate and cysteine metabolites to acetaminophen were significantly higher (P = 0.043, 0.004 and 0.010, respectively). In the model, acetaminophen CYP2E1-mediated clearance (cysteine and mercapturate) increased with lean body weight [LBW] (population mean [relative standard error] 0.0185 L/min [15 %], P < 0.01). Moreover, accelerated formation of the cysteine and mercapturate metabolites was found with increasing LBW (P < 0.001). Glucuronidation clearance (0.219 L/min [5 %]) and sulphation clearance (0.0646 L/min [6 %]) also increased with LBW (P < 0.001)., Conclusion: Obesity leads to lower acetaminophen concentrations and earlier and higher peak concentrations of acetaminophen cysteine and mercapturate. While a higher dose may be anticipated to achieve adequate acetaminophen concentrations, the increased CYP2E1-mediated pathway may preclude this dose adjustment.