Investigating the human metabolism of acetaminophen using UPLC and exact mass oa-TOF MS

Johnson, Kent C.; Plumb, Robert S.

doi:10.1016/j.jpba.2005.04.048

Cited by 103 publications

(55 citation statements)

References 17 publications

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“…Mercapturates are associated generically with tissue exposure to low molecular weight electrophilic precursors of GSH adducts (Hinchman and Ballatori, 1994). On the other hand, GSH conjugates are unsuitable biomarkers of metabolic activation in vivo because they are only very rarely eliminated in urine and seemingly only at very low concentrations (Johnson and Plumb, 2005). They have been found as N-acetylated derivatives (Tsuruda et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Quantifying the Metabolic Activation of Nevirapine in Patients by Integrated Applications of NMR and Mass Spectrometries

Srivastava¹,

Lian²,

Maggs³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Nevirapine (NVP), an antiretroviral drug, is associated with idiosyncratic hepatotoxicity and skin reactions. Metabolic pathways of haptenation and immunotoxicity mechanisms have been proposed. NVP is metabolized by liver microsomes to a reactive intermediate that binds irreversibly to protein and forms a GSH adduct. However, no reactive metabolite of NVP, trapped as stable thioether conjugates, has hitherto been identified in vivo. This study has defined the metabolism of NVP with respect to reactive intermediate formation in patients and a rat model of NVP-induced skin reactions. An integrated NMR and mass spectrometry approach has been developed to discover and quantify stable urinary metabolite biomarkers indicative of NVP bioactivation in patients. Two isomeric NVP mercapturates were identified in the urine of HIV-positive patients undergoing standard antiretroviral chemotherapy. The same conjugates were found in rat bile and urine. The mercapturates were isolated from rat bile and characterized definitively by NMR as thioethers substituted at the C-3 and exocyclic C-12 positions of the methylpyrido ring of NVP. It is proposed that NVP undergoes bioactivation to arene oxide and quinone methide intermediates. The purified major mercapturate was quantified by NMR and used to calibrate a mass spectrometric assay of the corresponding metabolite in patient urine. This is the first evidence for metabolic activation of NVP in humans, and only the second minimum estimate in patients of bioactivation of a widely prescribed drug associated with idiosyncratic toxicities. The method can be used as a template for comparative estimations of bioactivation of any drug in patients.

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Section: Discussionmentioning

confidence: 99%

Quantifying the Metabolic Activation of Nevirapine in Patients by Integrated Applications of NMR and Mass Spectrometries

Srivastava¹,

Lian²,

Maggs³

et al. 2009

Drug Metab Dispos

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“…However, the better results obtained by UPLC could be attributed to the detection mode, simple quadrupole versus TOF. Johnson and Plumb [113] investigated UPLC-MS for the detection and identification of human metabolites of acetaminophen in urine. A comparison with monolithic columns demonstrated that the UPLC-MS approach was approximately three times more sensitive and showed a larger number of metabolites than LC-MS (Fig.…”

Section: Fast Separations In Biological Fluidsmentioning

confidence: 99%

Fast analysis in liquid chromatography using small particle size and high pressure

Nguyen

Guillarme

Rudaz

et al. 2006

J of Separation Science

301

164

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ReviewFast analysis in liquid chromatography using small particle size and high pressureIn order to enhance chromatographic performances in terms of efficiency and rapidity, LC has recently evolved in the development of short columns packed with small particles (sub-2 lm) working at high pressures (A400 bar). This approach has been described 30 years ago according to the fundamental chromatographic equations. However, systems and columns compatible with such high pressures have been introduced in the market in 2004 only. Advantages of small particles working at high pressure will be discussed in terms of sensitivity, efficiency, resolution, and analysis time. Potential problems encountered with high pressure in terms of frictional heating and solvent compressibility will also be discussed even if systems working at a maximum pressure of 1000 bar are not influenced by these parameters and give reliable and reproducible results. Several applications will highlight the potential and interest of this new technology.

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“…To help the chromatographer achieve these objectives, smaller particle size stationary phases (which generate improved efficiency and reduced analysis times) and high-pressure LC systems (commonly referred to as ultra high pressure LC or ultra performance LC, UPLC) have been developed. Improved resolution and peak capacity for the analysis of many types of analytes such as peptides and proteins [1], metabolites [2] and drug substance impurities [3 -5] have now been demonstrated using sub-2 lm materials and UPLC systems.…”

Section: Introductionmentioning

confidence: 99%

Maximizing peak capacity and separation speed in liquid chromatography

Petersson¹,

Frank

Heaton

et al. 2008

J of Separation Science

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The practical effects of gradient time and flow rate on the peak capacities of a range of analytes of differing molecular weights (MWs) and physico-chemical properties have been evaluated using ultra high pressure LC instrumentation with sub-2 lm and superficially porous particle phases. Optimum peak capacity, in RP gradient LC, for small molecules, including typical pharmaceutical drugs and peptides with MWs up to 1300, was demonstrated at a maximum flow rate for a given gradient time (i.e. up to 40 min). Flow rates significantly higher than the optimum in the van Deemter plots and also higher than those typically employed by the majority of the chromatographers today are recommended for gradient LC (i.e. up to 1.0 mL/min on 50 -15062.1 mm 1.7 lm columns). This recommendation is applicable for temperatures above 408C, i.e. temperatures typically utilized for separations employing sub-2 lm particles to reduce column back pressure. Van Deemter and pseudo van Deemter plots were determined and combined with chromatographic gradient elution theory to explain our unexpected observations. The derived models exhibited good agreement between experimental and predicted peak capacities (absolute average error 4%, max. error 12%).

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Investigating the human metabolism of acetaminophen using UPLC and exact mass oa-TOF MS

Cited by 103 publications

References 17 publications

Quantifying the Metabolic Activation of Nevirapine in Patients by Integrated Applications of NMR and Mass Spectrometries

Quantifying the Metabolic Activation of Nevirapine in Patients by Integrated Applications of NMR and Mass Spectrometries

Fast analysis in liquid chromatography using small particle size and high pressure

Maximizing peak capacity and separation speed in liquid chromatography

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