Paracetamol Sulphate Research Articles

Clinical Pharmacology of Paracetamol in Infants and Children

Paracetamol (acetaminophen) has analgesic and antipyretic effects similar to those of aspirin but has only weak anti-inflammatory effects. It is a nonselective cyclooxygenase inhibitor which acts at the peroxidase site of the enzyme and is thus distinct among the nonsteroidal anti-inflammatory drugs. The major metabolites of paracetamol are paracetamol glucuronide and paracetamol sulphate and the minor metabolites are mercapturic acid cysteine conjugates and N-acetyl-p-benzoquinone imine. The last is a highly reactive intermediate and it reacts with sulfhydryl groups in glutathione and is harmless. Paracetamol may be administered orally, rectally, or intravenously. In infants, the oral dosing of paracetamol consist in a loading dose of 20 mg/kg following by subsequent doses of 10 to 15 mg/kg, and in children, the dose varies with the child age and body-weigh. Paracetamol has been found efficacy and safe in infants and children but it may induce adverse-effects. The elimination half-life of paracetamol is 11.0 and 4.38 hours in more immature preterm infants and in less immature preterm infants, respectively, and it is 3.45 hours in children. Propranolol interacts with drugs. The prophylaxis, treatment, and trials with paracetamol have been investigated in infants and children. Paracetamol may induce toxicity and it crosses the human placenta and migrates into the breast milk in significant amounts. The aim of this study in the review of paracetamol dosing, efficacy and safety, adverse-effects, metabolism, pharmacokinetics, drug interaction, prophylaxis, treatment, trials, toxicity in infants and children, and paracetamol transfer across the human placenta and migration into the breast milk.

Development of Urinary Assay Methods for the Estimation of Paracetamol Glucuronide and Paracetamol Sulphate in Preterm Neonates with Patent Ductus Arteriosus

Aims: This study aimed to develop a high-performance liquid chromatography (HPLC) technique for estimating paracetamol glucuronide and paracetamol sulphate in the urine samples of preterm neonates. Background: Validated methods exist for estimating the principal metabolites of paracetamol in older children and those with liver disease. Here, we have developed and validated a simple technique for estimating the same in urine samples of preterm neonates. Objective: The study aims to develop and validate a simple, reliable, and accurate HPLC technique for estimating urinary paracetamol glucuronide and paracetamol sulphate metabolites. Methods: Preterm neonates of either sex diagnosed with patent ductus arteriosus (PDA) receiving paracetamol intravenously at the dose of 15 mg/kg every six hours were recruited. We ran the samples under standardized chromatographic conditions and using various dilutions of the calibration standards. Measures of assay selectivity, linearity, accuracy, and precision were estimated. Results: We observed that the peaks for paracetamol glucuronide and paracetamol sulphate were distinguished from those of the drug-free urine samples. The results for both metabolites revealed good reproducibility, with a percent coefficient of variation (% CV) of 4.3 and 4.9 for the slope for paracetamol glucuronide and paracetamol sulphate, respectively. Similarly, we observed good linearity, as indicated by the correlation coefficients of 0.99 for the metabolites. The validation assays revealed that the method is linear, accurate, and precise over the defined concentration ranges. Conclusion: We demonstrated that HPLC has good accuracy, reliability, and precision, and it can be used for estimating the principal metabolites from urine samples in neonates for defining the ontogeny of conjugation enzymes and in paracetamol overdose.

A systematic review on a comparison between intravenous paracetamol and intravenous morphine sulfate for management of patients with trauma injuries

Introduction – Pain is known the most common complaint in emergency departments. Several studies are administered many different protocols to control pain in trauma patients. The aim of the study was to review the major relevant articles in case of application of intravenous paracetamol and intravenous morphine sulfate for management of patients with trauma injuries.

Propacetamol in dogs: First description of its pharmacokinetics after intravenous and oral administration

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.

Phenotyping SULT in Man: a Simple Metric Using Paracetamol as Probe

Introduction Sulfotransferase enzymes (SULT) catalyze sulfoconjugation of drugs, as well as endogenous mediators and environmental xenobiotics. To address the scarce evidence on sulfonation activity from clinical research, we developed a clinical metabolic phenotyping method using paracetamol as a probe substrate. Sulfonation accounts for up to 35% of the total paracetamol metabolism in humans and is mediated mainly by the activity of SULT1A1 and SULT1A3 (phenol sulfotransferases), in liver and small intestine respectively. Our aim was to estimate sulfonation capability of phenolic compounds and study its intraindividual variability in man. Population and Methods: This study was approved by the Portuguese National Ethics Committee. We recruited a population of 36 healthy adults (12 men and 24 women, 12 on oral contraceptives). Subjects received 1 g of oral paracetamol on three different occasions. Paracetamol and its metabolites (paracetamol sulfate, paracetamol glucuronate, paracetamol cysteine-S-conjugate and paracetamol mercapturate) were measured in plasma and spot urine samples using liquid chromatography-high resolution mass spectrometry. Paracetamol sulfonation index (PSI) was used to express SULT activity. PSI was calculated for urine (uPSI) and for plasma (pPSI) samples. We tested differences between groups using ANOVA and we used Pearson's correlation coefficient. Results The frequency distribution histograms of pPSI and uPSI were positively skewed in the studied population (Figure 1). The mean pPSI and uPSI were 0.43 (range 0.34 to 0.60) and 0.40 (range 0.31 to 0.55) respectively (Figure 2). PSI showed low intraindividual variability (mean coefficient of variation was 10% for pPSI and 13% for uPSI). There was a good correlation between values in plasma and spot urine samples (Pearson r=0.79). Urinary PSI was independent of factors not related to SULT activity, such as urine pH or eGFR. Gender and oral contraceptive intake had no impact on PSI. Discussion Our SULT phenotyping method is a simple non-invasive procedure requiring urine spot samples, using the safe and convenient drug paracetamol as a probe substrate, and with low intraindividual coefficient of variation. Although it will not give us mechanistic information, it will provide us an empirical measure of an individual's sulfonator status. To the best of our knowledge, our method provides the first in vivo empirical measure of an individual's phenol sulfonation capability and of its intraindividual variability.

Development of a Multimatrix UHPLC-MS/MS Method for the Determination of Paracetamol and Its Metabolites in Animal Tissues.

Paracetamol/acetaminophen (APAP) is one of the most popular pharmacologically active substances used as an analgesic and antipyretic agent. The metabolism of this drug occurs in the liver and leads to the formation of two main metabolites—glucuronic acid and sulfate derivate. Despite the wide use of paracetamol in veterinary medicine, a handful of analytical methods were published for the determination of paracetamol residues in animal tissues. In this paper, a multimatrix method has been developed for the determination of paracetamol and two metabolites—paracetamol sulfate (PS) and p-Acetamidophenyl β-D-glucuronide (PG). A validation procedure was conducted to verify method reliability and fit purpose as a tool for analyzing acetaminophen and metabolites in muscle, liver, lung, and kidney samples from different species of animals. Established validation parameters were in agreement with acceptable criteria laid by the European legislation. The initial significant matrix effect was successfully reduced by implementing an internal standard—4-Acetamidophenyl β-D-glucuronide-d3 (PG-d3, IS). The usefulness of the developed method was verified by analyzing samples from an experiment in which paracetamol was administrated to geese.

In vivo assessment of the drug interaction between sorafenib and paracetamol in rats

PurposeSorafenib is a multi-targeted tyrosine kinase inhibitor (TKI) used for the treatment of advanced renal cell carcinoma, hepatocellular carcinoma and radioactive iodine resistant thyroid carcinoma. Neoplastic diseases are the cause of pain, which may occur regardless of the stage of the disease. Paracetamol is a non-opioid analgesic used alone or in combination with opioids for the treatment of cancer pain. Numerous studies have pointed out changes in the pharmacokinetic parameters of TKIs when co-administered with paracetamol. The aim of the study was to assess drug–drug interactions (DDIs) between sorafenib and paracetamol.MethodsRats were divided into three groups, each consisting of eight animals. The first group received sorafenib (IIS), the second group received sorafenib + paracetamol (IS+PA), whereas the third group received only paracetamol (IIIPA). A single dose of sorafenib (100 mg/kg b.w.) and paracetamol (100 mg/kg b.w.) was administered orally. The plasma concentrations of sorafenib and its metabolite–N-oxide as well as paracetamol and its glucuronide and sulphate metabolites were measured using validated high-performance liquid chromatography (HPLC) method with ultraviolet detection.ResultsThe co-administration of sorafenib and paracetamol increased the maximum concentration (Cmax) of paracetamol by 33% (p = 0.0372). In the IS+ PA group the Cmax of paracetamol glucuronide was reduced by 48% (p = < 0.0001), whereas the Cmax of paracetamol sulphate was higher by 153% (p = 0.0012) than in the IIIPA group. Paracetamol increased sorafenib and sorafenib N-oxide Cmax by 60% (p = 0.0068) and 83% (p = 0.0023), respectively.ConclusionsA greater knowledge of DDI between sorafenib and paracetamol may help adjust dose properly and avoid toxicity effects in individual patients.

Immobilizing sulfotransferase 1A1 on magnetic microparticles and their evaluation using capillary electrophoresis.

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.

Transplacental transport of paracetamol and its phase II metabolites using the ex vivo placenta perfusion model

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.

The concomitant use of lapatinib and paracetamol - the risk of interaction

SummaryLapatinib is a tyrosine kinase inhibitor used for the treatment of breast cancer. Paracetamol is an analgesic commonly applied to patients with mild or moderate pain and fever. Cancer patients are polymedicated, which involves high risk of drug interactions during therapy. The aim of the study was to assess the interaction between lapatinib and paracetamol in rats. The rats were divided into three groups of eight animals in each. One group received lapatinib + paracetamol (IL + PA), another group received lapatinib (IIL), whereas the last group received paracetamol (IIIPA). A single dose of lapatinib (100 mg/kg b.w.) and paracetamol (100 mg/kg b.w.) was administered orally. Plasma concentrations of lapatinib, paracetamol and its metabolites – glucuronide and sulphate, were measured with the validated HPLC-MS/MS method and HPLC-UV method, respectively. The pharmacokinetic parameters of both drugs were calculated using non-compartmental methods. The co-administration of lapatinib and paracetamol increased the area under the plasma concentration-time curve (AUC) and the maximum concentration (Cmax) of lapatinib by 239.6% (p = 0.0030) and 184% (p = 0.0011), respectively. Lapatinib decreased the paracetamol AUC0-∞ by 48.8% and Cmax by 55.7%. In the IL + PA group the Cmax of paracetamol glucuronide was reduced, whereas the Cmax of paracetamol sulphate was higher than in the IIIPA group. Paracetamol significantly affected the enhanced plasma exposure of lapatinib. Additionally, lapatinib reduced the concentrations of paracetamol. The co-administration of lapatinib decreased the paracetamol glucuronidation but increased the sulphation. The findings of this study may be of clinical relevance to patients requiring analgesic therapy.

O-17 Transplacental transport of paracetamol and its metabolites using the ex-vivo human placenta perfusion model

Background In Europe, 50%–60% of pregnant women uses paracetamol (Dafalgan). While its use in pregnan-cy was considered safe, recent studies show an associ-ation between prenatal exposure to paracetamol and increased incidences of autism, cryptorchidism, asthma and attention deficit hyperactivity disorder in a dose and duration dependent manner1-3. Data on transplacental transfer and metabolism of paracetamol are limited. Methods In an ex vivo placenta perfusion model (closed circuit) (n=38), maternal-to-fetal and fetal-to-maternal transplacental transfer of paracetamol (PCM) and its me-tabolites, paracetamol sulfate (PCM-S) and paracetamol glucuronide (PCM-G), was determined at a concentration corresponding to the maximum (PCM: 30 µg/ml; PCM-S: 10 µg/ml; PCM-G: 25 µg/ml) and steady state (PCM: 10 µg/ml; PCM-S: 5 µg/ml; PCM-G: 12.5 µg/ml) plasma con-centrations in normal clinical use. Antipyrine 100 µg/mL was added as internal control. PCM, PCM-S, PCM-G and antipyrine concentrations in perfusion medium and pla-cental tissue were determined using HPLC and LC-MS. Samples were taken at 0, 3, 6, 10, 15, 20, 30 min then ev-ery 15 min until 150 min followed by every 30 min until 210 (PCM) or 360 min (PCM-S and PCM-G). Fetal-to-ma-ternal and maternal-to-fetal ratios were normalised for antipyrine for each time point. Tissue accumulation and recovery of the compounds was calculated. Statistical dif-ferences were assessed using ANOVA. Results The maternal-to-fetal as fetal-to-maternal trans-port of PCM was 44%–48%. For PCM-S, transplacental trans-fer was 38%–40% for maternal-to-fetal transfer and 28% for fetal-to-maternal transfer. PCM-G had a transfer of 31%–36% for maternal-to-fetal and 25% for fetal-to-maternal transfer. An equilibrium between the maternal and fetal concentrations was reached for PCM after 210 min for perfusion from maternal-to-fetal circulation. Fetal-to-ma-ternal transport of PCM-S and PCM-G was significantly slower then maternal-to-fetal transport. Extrapolation of maternal-to-fetal transport data till 360 min predict-ed equilibrium at 7.5 hour (PCM-S) and 9.5 hour (PCM-G). For fetal-to-maternal transport extrapolation of data till 210 min (PCM) and 360 min (PCM-S and PCM-G) predict-ed equilibrium for PCM after 270 min, PCM-S 36 hour and PCM-G 44 hour. PCM-S and PCM-G were converted to PCM by the placenta during the perfusions. Conclusion This study shows that PCM rapidly crosses the placental barrier via passive diffusion for both mater-nal-to-fetal and fetal-to-maternal transplacental transfer. PCM-S and PCM-G, larger and more hydrophilic mole-cules, cross the placenta at a significantly lower rate. For PCM-S and PCM-G fetal-to-maternal transport is signifi-cantly slower than maternal-to-fetal transport.

Paracetamol pharmacokinetics and metabolism in young women.

BackgroundThere is relevant between individual variability in paracetamol clearance in young women. In this pooled study, we focused on the population pharmacokinetic profile of intravenous paracetamol metabolism and its covariates in young women.MethodsPopulation PK parameters using non-linear mixed effect modelling were estimated in a pooled dataset of plasma and urine PK studies in 69 young women [47 at delivery, 8/47 again 10–15 weeks after delivery (early postpartum), and 7/8 again 1 year after delivery (late postpartum), 22 healthy female volunteers with or without oral contraceptives].ResultsPopulation PK parameters were estimated based on 815 plasma samples and 101 urine collections. Compared to healthy female volunteers (reference group) not on oral contraceptives, being at delivery was the most significant covariate for clearance to paracetamol glucuronide (Factor = 2.03), while women in early postpartum had decreased paracetamol glucuronidation clearance (Factor = 0.55). Women on contraceptives showed increased paracetamol glucuronidation clearance (Factor = 1.46). The oestradiol level did not further affect this model. Being at delivery did not prove significant for clearance to paracetamol sulphate, but was higher in pregnant women who delivered preterm (<37 weeks, Factor = 1.34) compared to term delivery and non-pregnant women. Finally, clearance of unchanged paracetamol was dependent on urine flow rate.ConclusionsCompared to healthy female volunteers not on oral contraceptives, urine paracetamol glucuronidation elimination in young women is affected by pregnancy (higher), early postpartum (lower) or exposure to oral contraceptives (higher), resulting in at least a two fold variability in paracetamol clearance in young women.

First pass intestinal and liver metabolism of paracetamol in a microfluidic platform coupled with a mathematical modeling as a means of evaluating ADME processes in humans.

We developed a microfluidic platform to investigate paracetamol intestinal and liver first pass metabolism. This approach was coupled with a mathematical model to estimate intrinsic in vitro parameters and to predict in vivo processes. The kinetic modeling estimated the paracetamol and paracetamol sulfate permeabilities, the sulfate and glucuronide effluxes in the intestine compartment. Based on a gut model, we estimated intrinsic intestinal clearance of between 26 and 77 L/h for paracetamol in humans, a permeability of 10 L/h, and a gut availability between 0.17 and 0.53 (compared to 0.95-1 in vivo). The role played by the liver in paracetamol metabolism was estimated via in vitro intrinsic clearances of 7.6, 13.6, and 11.5 µL/min/10(6) cells for HepG2/C3a, rat primary hepatocytes, and human primary hepatocytes, respectively. Based on a parallel tube model to describe the liver, the paracetamol hepatic clearance, and the paracetamol hepatic availability in humans were estimated at 6.5 mL/min/kg of bodyweight (BDW) and 0.7, respectively (when compared to 5 mL/min/kg of BDW and 0.77 to 0.88 for in vivo values, respectively). The drug availability was predicted ranging between 0.24 and 0.41 (0.88 in vivo). The overall approach provided a first step in an integrated strategy combining in silico/in vitro methods based on microfluidic for evaluating drug absorption, distribution and metabolism processes.

Evaluation of a Liver Microfluidic Biochip to Predict In Vivo Clearances of Seven Drugs in Rats

AbstractWe investigated metabolic clearances of phenacetin, midazolam, propranolol, paracetamol, tolbutamide, caffeine, and dextromethorphan by primary rat hepatocytes cultivated in microfluidic biochips. The levels of mRNA of the HNF4α, PXR, AHR, CYP3A1, and CYP1A2 genes were enhanced in the biochip cultures when compared with postextraction levels. We measured a high and rapid adsorption on the biochip walls and inside the circuit for dextromethorphan and midazolam, a moderate adsorption for phenacetin and propranolol, and a low adsorption for caffeine, tolbutamide, and paracetamol. Drug biotransformations were demonstrated by the formations of specific metabolites such as paraxanthyne (caffeine), paracetamol (phenacetin), 1-OH midazolam (midazolam), paracetamol sulfate (paracetamol and phenacetin), and dextrorphan (dextromethorphan). We used a pharmacokinetic model to estimate the adsorption and in vitro intrinsic drug clearance values. We calculated in vitro intrinsic clearance values of 0.5, 3, 12.5, 83, 100, 160, and 900 μL/min per 106 cells for the tolbutamide, caffeine, paracetamol, dextromethorphan, phenacetin, midazolam, and propranolol, respectively. A second model describing the liver as a well-stirred compartment predicted in vivo hepatic clearances of 0.1, 13.8, 30, 44.1, 61, 72, 85, and 61 mL/min per kg of body mass for the tolbutamide, caffeine, paracetamol, midazolam, dextromethorphan, phenacetin, and propranolol, respectively. These values appeared consistent with previously reported data. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:706–718, 2014

Detection and Follow-Up, after Partial Liver Resection, of the Urinary Paracetamol Metabolites by Proton NMR Spectroscopy

Background: Combination drug therapy is often used to achieve optimal analgesia in surgery. Paracetamol can be used as one component of an analgesic regime following hepatic resection. Objective: This study was designed to investigate paracetamol and its metabolites by proton NMR spectroscopy in patient urine and to assess whether N-acetyl-p-benzoquinone imine (NAPQI, a hepatotoxic metabolite) formation is increased after liver resection. Method: We studied the excretion of acetaminophen and its metabolites by 5 patients who were operated on for partial liver resection by proton NMR spectroscopy. As an intravenous infusion 1 g of paracetamol was given over 15 min every 6 h during 48 h. The first injection was given in the operating theatre after liver resection was completed. Urine samples were collected before injection (T1) and 24 and 48 h after the first injection (T2 and T3); the samples were frozen and kept at -20°C up to the analysis by NMR spectroscopy. Results: Metabolites of the paracetamol were detected for all patients. Among the discerned metabolites, 4 were identified as metabolites of paracetamol: paracetamol glucuronide, paracetamol sulfate, N-acetyl-<smlcap>L-</smlcap>cysteinyl paracetamol (metabolite of NAPQI) and paracetamol. Their ratios, respectively, were: 46-82.9, 12.6-30.0, 0.5-5.5 and 1.43-3.54%. Conclusion: This study showed that there was no increase in the formation of toxic metabolite (NAPQI) after treatment with paracetamol in these few cases of liver resections. A larger study is necessary to confirm these results.

Pharmacokinetics of paracetamol and its metabolites in women at delivery and post‐partum

A recent report on intravenous (i.v.) paracetamol pharmacokinetics (PK) showed a higher total clearance in women at delivery compared with non-pregnant women. To describe the paracetamol metabolic and elimination routes involved in this increase in clearance, we performed a population PK analysis in women at delivery and post-partum in which the different pathways were considered. Population PK parameters using non-linear mixed effect modelling were estimated in a two-period PK study in women to whom i.v. paracetamol (2 g loading dose followed by 1 g every 6 h up to 24 h) was administered immediately following Caesarean delivery and in a subgroup of the same women to whom single 2 g i.v.loading dose was administered 10-15 weeks post-partum. Population PK analysis was performed based on 255 plasma and 71 urine samples collected in 39 women at delivery and in eight of these 39 women 12 weeks post-partum. Total clearance was higher in women at delivery compared with 12th post-partum week (21.1 vs. 11.7 l h⁻¹) due to higher clearances to paracetamol glucuronide (11.6 vs. 4.76 l h⁻¹), to oxidative metabolites (4.95 vs. 2.77 l h⁻¹) and of unchanged paracetamol (1.15 vs. 0.75 l h⁻¹). In contrast, there was no difference in clearance to paracetamol sulphate. The increased total paracetamol clearance at delivery is caused by a disproportional increase in glucuronidation clearance and a proportional increase in clearance of unchanged paracetamol and in oxidation clearance, of which the latter may potentially limit further dose increase in this patient group.

Investigating paracetamol pharmacokinetics using venous and capillary blood and saliva sampling

The aim of this study was to develop, validate and apply a high performance liquid chromatography (HPLC) assay for analysis of paracetamol, paracetamol glucuronide and paracetamol sulfate in plasma (venous and capillary) and saliva to study paracetamol pharmacokinetics in healthy volunteers. Samples were prepared using protein precipitation and analysed using reverse phase HPLC with UV detection. This assay was applied to venous and capillary plasma and saliva samples from 20 healthy volunteers after paracetamol 1g four times daily for three days. The HPLC assay for paracetamol and its metabolites was found to be sensitive and selective in plasma and saliva samples over the range 0.05-50 mg/l with an inter- and intraday precision and accuracy within 11.2% and 11.1%, respectively. Mean recoveries for all analytes were > 88%. A study of paracetamol pharmacokinetics in healthy volunteers found close agreement between the sampling matrices for paracetamol and metabolites (metabolites were not detected in saliva). The value for area under the concentration-time curve over the 6h dosing interval of venous plasma (45.3±12.9mg/l.h) was significantly higher than that observed for capillary plasma (33.8±12.9mg/l.h) or saliva (35.1±9.4mg/l.h; P>0.01). Capillary blood and saliva collection were found to be reliable sampling matrices for the evaluation of paracetamol pharmacokinetics, although paracetamol metabolites were not detected in saliva.

Inhibition of the hepatic uptake of paracetamol sulphate by anionic compounds.

The effect of anionic compounds on the hepatic uptake of paracetamol sulphate, a conjugative metabolite of paracetamol, has been studied. Hepatic uptake of paracetamol sulphate by isolated hepatocytes was inhibited by bromosulphophthalein, dibromosulphophthalein and p-nitrophenyl sulphate, but not by probenecid or cholic acid. Bromosulphophthalein and dibromosulphophthalein also inhibited the uptake of paracetamol sulphate in the rat isolated perfused liver. Saturable uptake of paracetamol sulphate was also observed in the absence of inorganic sulphate. The uptake of paracetamol sulphate was reduced by 1 and 10 mM inorganic sulphate. Bromosulphophthalein and p-nitrophenyl sulphate inhibited the uptake of paracetamol sulphate in the absence of inorganic sulphate. These results indicate that paracetamol sulphate shares a transporter with bromosulphophthalein, dibromosulphophthalein and p-nitrophenyl sulphate, all of which contain the sulphate or sulphonate group. Therefore, the sulphate or sulphonate moiety might be crucial for interaction with the transporter, and mutual inhibition of hepatic uptake among these compounds is likely.

Pharmacokinetics of Intravenous Paracetamol in Elderly Patients

Intravenous paracetamol (N-acetyl-paraminophenol, acetaminophen) is a widely used nonopioid analgesic which has become popular in the treatment of pain in many patient groups, including the elderly. Although intravenous paracetamol has been studied widely in clinical analgesia studies, there is little information on its pharmacokinetics in the elderly. We designed this study to determine the pharmacokinetics of intravenous paracetamol in very old patients and to compare them with that of younger patients. We also considered the effect of adenosine triphosphate-binding cassette G2 protein (ABCG2) genotype and renal function on paracetamol pharmacokinetics in these patients. We compared the pharmacokinetics of intravenous paracetamol in four groups of ten patients, aged 20-40, 60-70, 70-80 and 80-90 years, undergoing orthopaedic surgery. Paracetamol 1000 mg was given by infusion over 15 minutes. Plasma concentrations of paracetamol and its glucuronide and sulphate conjugates were measured for 24 hours with a high-performance liquid chromatographic method and ABCG2 genotype was determined. Glomerular filtration rate (GFR) was estimated from age, sex and serum creatinine of the patient. In the group aged 80-90 years, the mean value of the area under the plasma concentration-time curve extrapolated to infinity (AUC(∞)) of paracetamol was 54-68% higher than in the two youngest groups. Paracetamol clearance showed a statistically significant dependence on age group, whereas volume of distribution during elimination and elimination half-life were associated with age group and sex, respectively. Based on mean AUC(∞) of paracetamol glucuronide and paracetamol sulphate, the oldest patients had 1.3- to 1.5-fold greater exposure to these metabolites than patients aged 20-40 years. ABCG2 genotype did not affect paracetamol pharmacokinetics. There was a linear correlation between the values of AUC(∞) of paracetamol, its glucuronide and sulphate metabolites and GFR. Age and sex are important factors affecting the pharmacokinetics of paracetamol. The higher the age of the patient, the higher is the exposure to paracetamol. Female sex is associated with increased paracetamol concentrations but ABCG2 genotype does not seem to affect paracetamol pharmacokinetics. Trial registration number (EudraCT): 2006-001917-14.

Effects of imatinib mesylate on the pharmacokinetics of paracetamol (acetaminophen) in Korean patients with chronic myelogenous leukaemia

The major objective of the present study was to investigate the effect of imatinib on the pharmacokinetics of paracetamol in patients with chronic myelogenous leukaemia (CML). Patients (n = 12) received a single oral dose of acetaminophen 1000 mg on day 1 (control). On days 2-8, imatinib 400 mg was administered daily. On day 8 (treatment), another 1000 mg dose of paracetamol was administered 1 h after the morning dose of imatinib 400 mg. Blood and urine samples were collected for bioanalytical analyses. The area under the plasma concentration-time curve (AUC) for paracetamol, paracetamol glucuronide and paracetamol sulphate under control conditions was similar to that after treatment with imatinib; the 90% confidence interval of the log AUC ratio was within 0.8 to 1.25. Urinary excretion of paracetamol, paracetamol glucuronide and paracetamol sulphate was also unaffected by imatinib. The pharmacokinetics of paracetamol and imatinib in Korean patients with CML were similar to previous pharmacokinetic results in white patients with CML. Co-administration of a single dose of paracetamol and multiple doses of imatinib was well tolerated and safety profiles were similar to those of either drug alone. The pharmacokinetics of paracetamol and its major metabolites in the presence of imatinib were similar to those of the control conditions and the combination was well tolerated. These findings suggest that imatinib can be safely administered with paracetamol without dose adjustment of either drug.