Simultaneous quantification of acetaminophen and five acetaminophen metabolites in human plasma and urine by high-performance liquid chromatography–electrospray ionization–tandem mass spectrometry: Method validation and application to a neonatal pharmacokinetic study

Cook, Sarah F.; King, Amber D.; Anker, John N. van den; Wilkins, Diana G.

doi:10.1016/j.jchromb.2015.10.013

Cited by 52 publications

(66 citation statements)

References 33 publications

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“…Plasma and urinary concentrations of paracetamol, paracetamol-glucuronide, paracetamol-sulfate, paracetamol-cysteine, and paracetamol- N -acetylcysteine were determined by high-performance liquid chromatography-tandem mass spectrometry according to previously reported methods [19]. Mean intra- and inter-assay accuracy ranged from 85 to 111 %, and intra- and inter-assay imprecision did not exceed 15 % coefficient of variation (CV).…”

Section: Methodsmentioning

confidence: 99%

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Neonatal Maturation of Paracetamol (Acetaminophen) Glucuronidation, Sulfation, and Oxidation Based on a Parent–Metabolite Population Pharmacokinetic Model

et al. 2016

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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 (CLformation) 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). CLformation for all metabolites increased with weight; CLformation for glucuronidation and oxidation also increased with postnatal age. At the mean weight (2.3 kg) and postnatal age (7.5 days), CLformation 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 CLformation as a fraction of total individual paracetamol clearance showed that, on average, fractional oxidation CLformation 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.

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Section: Methodsmentioning

confidence: 99%

“…Paracetamol ( N -acetyl- p -aminophenol, acetaminophen) is used to manage mild-to-moderate pain in neonates [1, 2]. Intravenous formulations of the drug have recently become available but have rapidly been adopted into clinical practice for applications in which enteral delivery is unsuitable, such as postoperative analgesia [3].…”

Section: Introductionmentioning

confidence: 99%

Neonatal Maturation of Paracetamol (Acetaminophen) Glucuronidation, Sulfation, and Oxidation Based on a Parent–Metabolite Population Pharmacokinetic Model

et al. 2016

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“…Finally, there may be differences in the methods used to quantify the concentrations between the two datasets that are contributing to the bias. Both datasets used HPLC though the original dataset used MS/MS for detection and the external dataset used UV detection [4,7]. Additionally, the original dataset had a lower limit of quantification (LLOQ) of 0.05 μg ml À1 while the data from the external dataset had a LLOQ of 2 μg ml À1 , which is to be expected with the two types of detection used.…”

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Evident bias in a paracetamol metabolite population pharmacokinetic model applied to an external dataset

Roberts

Linakis

Liu

et al. 2018

Brit J Clinical Pharma

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Keywords acetaminophen, external validation, neonate, NONMEM, paracetamol, population pharmacokinetics Paracetamol (acetaminophen) is commonly used to manage mild and moderate pain in neonates [1]. There has been extensive work exploring the pharmacokinetics of paracetamol in neonates, but few studies have also evaluated the metabolites in conjunction with the parent drug. A recently published population pharmacokinetic model successfully characterized the pharmacokinetics of paracetamol and its metabolites in the plasma and urine of preterm and term neonates and indicated that both weight and postnatal age played an important role in describing the interindividual variability [2]. The FDA suggests that an external validation is the most 'stringent' form of validation for a pharmacokinetic model [3]. Therefore, this analysis sought to validate the previously published model with an external cohort of preterm and term neonates to verify the extrapolation of this model to broader clinical settings.Patients for the validation dataset were recruited from the Gasthuisberg Neonatal Intensive Care Unit, following approval of the study by the local ethics board of the University Hospital, Leuven, Belgium. Informed consent was obtained from the parents. The validation dataset included a total of 793 measured urine and plasma concentrations (353 plasma paracetamol, 132 urinary paracetamol-glucuronide, 154 urinary paracetamol-sulfate and 154 urinary paracetamol concentrations) from 54 neonates with a median postconceptual age (sum of gestational age and postnatal age) of 36 weeks (range: 27-60) and a median weight of 2.5 kg (range: 0.5-6.3) [4]. Thirty of the neonates only had plasma paracetamol samples available. None of the patients had plasma metabolite concentrations measured.The published neonatal paracetamol metabolite model was implemented using non-linear mixed effects modelling software (NONMEM v 7.3; ICON Development Solutions, Elliot City, MD, USA) as previously described [2]. Briefly, the model had a single compartment for plasma paracetamol, 3-plasma compartments for the metabolites (paracetamol-glucuronide, paracetamol-sulfate and the combined oxidative pathway metabolites paracetamol-cysteine and paracetamol-N-acetylcysteine) and 4-urine compartments (one for paracetamol and each of the metabolites).

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“…The prominent fragment ion at m / z 364.3 of the single‐charge peak for Zn‐DTPA probably formed by cleavage of two carboxyl groups from the parent ion structure, while that at m / z 204.5 of the double‐charge peak possibly resulted from the loss of one carboxyl group. Multiple reaction monitoring transitions for analyte quantification were selected based on the ability to provide acceptable specificity and optimal product ion abundance for maximum sensitivity (Cook, King, van den Anker, & Wilkins, ). The LLOQ (1 μg/mL) of our method was above the typical sensitivity obtained by this instrument, probably owing to poor ionization of this complex within the electrospray.…”

Section: Resultsmentioning

confidence: 99%

Developing a robust LC–MS/MS method to quantify Zn‐DTPA, a zinc chelate in human plasma and urine

Meng

Guo³

et al. 2018

Biomedical Chromatography

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Quantitation of Zn-DTPA (zinc diethylenetriamene pentaacetate, a metal chelate) in complex biological matrix is extremely challenging on account of its special physiochemical properties. This study aimed to develop a robust and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determination of Zn-DTPA in human plasma and urine. The purified samples were separated on Proteonavi (250 × 4.6 mm, 5 μm; Shiseido, Ginza, Tokyo, Japan) and a C guard column. The mobile phase consisted of methanol-2 mm ammonium formate (pH 6.3)-ammonia solution (50:50:0.015, v/v/v), flow rate 0.45 mL/min. The linear concentration ranges of the calibration curves for Zn-DTPA were 1-100 μg/mL in plasma and 10-2000 μg/mL in urine. The intra- and inter-day precisions for quality control (QC) samples were from 1.8 to 14.6% for Zn-DTPA and the accuracies for QC samples were from -4.8 to 8.2%. This method was fully validated and successfully applied to the quantitation of Zn-DTPA in plasma and urine samples of a healthy male volunteer after intravenous infusion administration of Zn-DTPA. The result showed that the concentration of Zn-DTPA in urine was about 20 times that in plasma, and Zn-DTPA was completely (94.7%) excreted through urine in human.

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Simultaneous quantification of acetaminophen and five acetaminophen metabolites in human plasma and urine by high-performance liquid chromatography–electrospray ionization–tandem mass spectrometry: Method validation and application to a neonatal pharmacokinetic study

Cited by 52 publications

References 33 publications

Neonatal Maturation of Paracetamol (Acetaminophen) Glucuronidation, Sulfation, and Oxidation Based on a Parent–Metabolite Population Pharmacokinetic Model

Neonatal Maturation of Paracetamol (Acetaminophen) Glucuronidation, Sulfation, and Oxidation Based on a Parent–Metabolite Population Pharmacokinetic Model

Evident bias in a paracetamol metabolite population pharmacokinetic model applied to an external dataset

Developing a robust LC–MS/MS method to quantify Zn‐DTPA, a zinc chelate in human plasma and urine

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