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3 Hydroxycotinine

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Marilyn A Huestis – 1st expert on this subject based on the ideXlab platform

  • A validated method for the determination of nicotine, cotinine, trans‐3′‐Hydroxycotinine, and norcotinine in human plasma using solid‐phase extraction and liquid chromatography‐atmospheric pressure chemical ionization‐mass spectrometry
    Journal of Mass Spectrometry, 2020
    Co-Authors: Marilyn A Huestis

    Abstract:

    A liquid chromatographic-mass spectrometric method for the simultaneous determination of nicotine, cotinine, trans-3′-Hydroxycotinine, and norcotinine in human plasma was developed and validated. Analytes and deuterated internal standards were extracted from human plasma using solid-phase extraction and analyzed by liquid chromatography/atmospheric pressure chemical ionization-mass spectrometric detection with selected ion monitoring (SIM). Limits of detection and quantification were 1.0 and 2.5 ng/ml, respectively, for all analytes. Linearity ranged from 2.5 to 500 ng/ml of human plasma using a weighting factor of 1/x; correlation coefficients for the calibration curves were > 0.99. Intra- and inter-assay precision and accuracy were < 15.0%. Recoveries were 108.2–110.8% nicotine, 95.8–108.7% cotinine, 90.5–99.5% trans-3′-Hydroxycotinine, and 99.5–109.5% norcotinine. The method was also partially validated in bovine serum, owing to the difficulty of obtaining nicotine-free human plasma for the preparation of calibrators and quality control (QC) samples. This method proved to be robust and accurate for the quantification of nicotine, cotinine, trans-3′-Hydroxycotinine, and norcotinine in human plasma collected in clinical studies of acute nicotine effects on brain activity and on the development of neonates of maternal smokers. Copyright © 2006 John Wiley & Sons, Ltd.

  • nicotine metabolite ratio 3 Hydroxycotinine cotinine in plasma and urine by different analytical methods and laboratories implications for clinical implementation
    Cancer Epidemiology Biomarkers & Prevention, 2015
    Co-Authors: Marilyn A Huestis, Sharon E Murphy, Julie Anne Tanner, Maria Novalen, Peter Jatlow, Jaakko Kaprio, Aino Kankaanpaa, Laurence Galanti, Cristiana Stefan

    Abstract:

    The highly genetically variable enzyme CYP2A6 metabolizes nicotine to cotinine (COT) and COT to trans-3‘-Hydroxycotinine (3HC). The nicotine metabolite ratio (NMR, 3HC/COT) is commonly used as a biomarker of CYP2A6 enzymatic activity, rate of nicotine metabolism, and total nicotine clearance; NMR is associated with numerous smoking phenotypes, including smoking cessation. Our objective was to investigate the impact of different measurement methods, at different sites, on plasma and urinary NMR measures from ad libitum smokers.Plasma (n = 35) and urine (n = 35) samples were sent to eight different laboratories, which used similar and different methods of COT and 3HC measurements to derive the NMR. We used Bland-Altman analysis to assess agreement, and Pearson correlations to evaluate associations, between NMR measured by different methods.Measures of plasma NMR were in strong agreement between methods according to Bland-Altman analysis (ratios, 0.82-1.16) and were highly correlated (all Pearson r > 0.96, P < 0.0001). Measures of urinary NMR were in relatively weaker agreement (ratios 0.62-1.71) and less strongly correlated (Pearson r values of 0.66-0.98, P < 0.0001) between different methods. Plasma and urinary COT and 3HC concentrations, while weaker than NMR, also showed good agreement in plasma, which was better than that in urine, as was observed for NMR.Plasma is a very reliable biologic source for the determination of NMR, robust to differences in these analytical protocols or assessment site.Together this indicates a reduced need for differential interpretation of plasma NMR results based on the approach used, allowing for direct comparison of different studies.

  • Nicotine Metabolite Ratio (3Hydroxycotinine/Cotinine) in Plasma and Urine by Different Analytical Methods and Laboratories: Implications for Clinical Implementation.
    Cancer Epidemiology Biomarkers & Prevention, 2015
    Co-Authors: Julie Anne Tanner, Marilyn A Huestis, Sharon E Murphy, Cristiana Stefan, Maria Novalen, Peter Jatlow, Jaakko Kaprio, Aino Kankaanpaa, Laurence Galanti, Tony P. George

    Abstract:

    The highly genetically variable enzyme CYP2A6 metabolizes nicotine to cotinine (COT) and COT to trans-3‘-Hydroxycotinine (3HC). The nicotine metabolite ratio (NMR, 3HC/COT) is commonly used as a biomarker of CYP2A6 enzymatic activity, rate of nicotine metabolism, and total nicotine clearance; NMR is associated with numerous smoking phenotypes, including smoking cessation. Our objective was to investigate the impact of different measurement methods, at different sites, on plasma and urinary NMR measures from ad libitum smokers.Plasma (n = 35) and urine (n = 35) samples were sent to eight different laboratories, which used similar and different methods of COT and 3HC measurements to derive the NMR. We used Bland-Altman analysis to assess agreement, and Pearson correlations to evaluate associations, between NMR measured by different methods.Measures of plasma NMR were in strong agreement between methods according to Bland-Altman analysis (ratios, 0.82-1.16) and were highly correlated (all Pearson r > 0.96, P < 0.0001). Measures of urinary NMR were in relatively weaker agreement (ratios 0.62-1.71) and less strongly correlated (Pearson r values of 0.66-0.98, P < 0.0001) between different methods. Plasma and urinary COT and 3HC concentrations, while weaker than NMR, also showed good agreement in plasma, which was better than that in urine, as was observed for NMR.Plasma is a very reliable biologic source for the determination of NMR, robust to differences in these analytical protocols or assessment site.Together this indicates a reduced need for differential interpretation of plasma NMR results based on the approach used, allowing for direct comparison of different studies.

Neal L Benowitz – 2nd expert on this subject based on the ideXlab platform

  • variation in trans 3 Hydroxycotinine glucuronidation does not alter the nicotine metabolite ratio or nicotine intake
    PLOS ONE, 2013
    Co-Authors: Qian Zhou, Neal L Benowitz, Rachel F Tyndale, Jasjit S Ahluwalia

    Abstract:

    Background
    CYP2A6 metabolizes nicotine to its primary metabolite cotinine and also mediates the metabolism of cotinine to trans-3′-Hydroxycotinine (3HC). The ratio of 3HC to cotinine (the “nicotine metabolite ratio”, NMR) is an in vivo marker for the rate of CYP2A6 mediated nicotine metabolism, and total nicotine clearance, and has been associated with differences in numerous smoking behaviors. The clearance of 3HC, which affects the NMR, occurs via renal excretion and metabolism by UGT2B17, and possibly UGT2B10, to 3HC-glucuronide. We investigated whether slower 3HC glucuronidation alters NMR, altering its ability to predict CYP2A6 activity and reducing its clinical utility.

  • High dose transdermal nicotine for fast metabolizers of nicotine: a proof of concept placebo-controlled trial.
    Nicotine & Tobacco Research, 2012
    Co-Authors: Robert A. Schnoll, Rachel F Tyndale, E. Paul Wileyto, Frank T. Leone, Neal L Benowitz

    Abstract:

    Introduction:
    Smokers with a faster rate of nicotine metabolism, estimated using the ratio of 3′-Hydroxycotinine (3-HC) to cotinine, have lower plasma nicotine levels and are more likely to relapse with 21 mg nicotine patch therapy, than smokers with slower rates of nicotine metabolism. Thus, faster metabolizers of nicotine may require a higher nicotine patch dose to achieve cessation.

  • determination of the nicotine metabolites cotinine and trans 3 Hydroxycotinine in biologic fluids of smokers and non smokers using liquid chromatography tandem mass spectrometry biomarkers for tobacco smoke exposure and for phenotyping cytochrome p45
    Journal of Chromatography B, 2011
    Co-Authors: Peyton Jacob, Lisa Yu, Minjiang Duan, Lita Ramos, Olivia Yturralde, Neal L Benowitz

    Abstract:

    Abstract The nicotine metabolite cotinine is widely used to assess the extent of tobacco use in smokers, and secondhand smoke exposure in non-smokers. The ratio of another nicotine metabolite, trans-3′-Hydroxycotinine, to cotinine in biofluids is highly correlated with the rate of nicotine metabolism, which is catalyzed mainly by cytochrome P450 2A6 (CYP2A6). Consequently, this nicotine metabolite ratio is being used to phenotype individuals for CYP2A6 activity and to individualize pharmacotherapies for tobacco addiction. In this paper we describe a highly sensitive liquid chromatography–tandem mass spectrometry method for determination of the nicotine metabolites cotinine and trans-3′-Hydroxycotinine in human plasma, urine, and saliva. Lower limits of quantitation range from 0.02 to 0.1 ng/mL. The extraction procedure is straightforward and suitable for large-scale studies. The method has been applied to several thousand biofluid samples for pharmacogenetic studies and for studies of exposure to low levels of secondhand smoke. Concentrations of both metabolites in urine of non-smokers with different levels of secondhand smoke exposure are presented.

Diaa M. Shakleya – 3rd expert on this subject based on the ideXlab platform

  • simultaneous quantification of nicotine cotinine trans 3 Hydroxycotinine norcotinine and mecamylamine in human urine by liquid chromatography tandem mass spectrometry
    Clinica Chimica Acta, 2012
    Co-Authors: Karl B Scheidweiler, Diaa M. Shakleya, Marilyn A Huestis

    Abstract:

    Abstract Background Mecamylamine is a nicotine antagonist under investigation in combination with nicotine replacement for smoking treatment. Methods A simple, rapid and reliable liquid chromatography tandem mass spectrometry (LCMSMS) method was developed and validated for quantifying nicotine, cotinine, trans-3′-Hydroxycotinine, norcotinine and mecamylamine in human urine. Chromatography was performed on a Synergi PolarRP column with a gradient of 0.1% formic acid and 0.1% formic acid in acetonitrile at 0.25 ml/min with an 8-min total runtime. Analytes were monitored by positive mode electrospray ionization and multiple reaction monitoring mass spectrometry. Results Linear dynamic ranges were 1–500 ng/ml for nicotine and norcotinine, 0.5–500 ng/ml for trans-3′-Hydroxycotinine, 0.2–500 ng/ml for cotinine, and 0.1–100 ng/ml for mecamylamine; correlation coefficients were consistently greater than 0.99, and all calibrator concentrations were within 20% of target. Extensive endogenous and exogenous interferences were evaluated. At 3 concentrations spanning the linear dynamic range of the assay, mean extraction efficiencies from urine were 55.1–109.1% with analytical recovery (bias) 82.0–118.7% and total imprecision of 0.7–9.1%. Analytes were stable for 24 h at room temperature, 72 h at 4 °C, 72 h in autosampler at 15 °C and after three freeze/thaw cycles. Conclusion This method is useful for monitoring mecamylamine, nicotine and nicotine metabolites in smoking cessation and other clinical nicotine research.

  • Simultaneous quantification of nicotine, cotinine, trans-3‘-Hydroxycotinine, norcotinine and mecamylamine in human urine by liquid chromatography-tandem mass spectrometry.
    Clinica chimica acta; international journal of clinical chemistry, 2012
    Co-Authors: Karl B Scheidweiler, Diaa M. Shakleya, Marilyn A Huestis

    Abstract:

    Mecamylamine is a nicotine antagonist under investigation in combination with nicotine replacement for smoking treatment.
    A simple, rapid and reliable liquid chromatography tandem mass spectrometry (LCMSMS) method was developed and validated for quantifying nicotine, cotinine, trans-3‘-Hydroxycotinine, norcotinine and mecamylamine in human urine. Chromatography was performed on a Synergi PolarRP column with a gradient of 0.1% formic acid and 0.1% formic acid in acetonitrile at 0.25 ml/min with an 8-min total runtime. Analytes were monitored by positive mode electrospray ionization and multiple reaction monitoring mass spectrometry.
    Linear dynamic ranges were 1-500 ng/ml for nicotine and norcotinine, 0.5-500 ng/ml for trans-3‘-Hydroxycotinine, 0.2-500 ng/ml for cotinine, and 0.1-100 ng/ml for mecamylamine; correlation coefficients were consistently greater than 0.99, and all calibrator concentrations were within 20% of target. Extensive endogenous and exogenous interferences were evaluated. At 3 concentrations spanning the linear dynamic range of the assay, mean extraction efficiencies from urine were 55.1-109.1% with analytical recovery (bias) 82.0-118.7% and total imprecision of 0.7-9.1%. Analytes were stable for 24h at room temperature, 72 h at 4 °C, 72 h in autosampler at 15 °C and after three freeze/thaw cycles.
    This method is useful for monitoring mecamylamine, nicotine and nicotine metabolites in smoking cessation and other clinical nicotine research.
    Published by Elsevier B.V.

  • Optimization and validation of a liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of nicotine, cotinine, trans-3′-Hydroxycotinine and norcotinine in human oral fluid
    Analytical and Bioanalytical Chemistry, 2009
    Co-Authors: Diaa M. Shakleya, Marilyn A Huestis

    Abstract:

    An analytical procedure was developed and validated for the simultaneous identification and quantification of nicotine, cotinine, trans –3′-Hydroxycotinine, and norcotinine in 0.5 mL of human oral fluid collected with the Quantisal™ oral fluid collection device. Solid phase extraction and liquid chromatography-tandem mass spectrometry with multiple reaction monitoring were utilized. Endogenous and exogenous interferences were extensively evaluated. Limits of quantification were empirically identified by decreasing analyte concentrations. Linearity was from 1 to 2,000 ng/mL for nicotine and norcotinine, 0.5 to 2,000 ng/mL for trans –3′-Hydroxycotinine, and 0.2 to 2,000 ng/mL for cotinine. Correlation coefficients for calibration curves were >0.99 and analytes quantified within ±13% of target at all calibrator concentrations. Suitable analytical recovery (>91%) was achieved with extraction efficiencies >56% and matrix effects