Small Molecule Quantification by Liquid Chromatography-Mass Spectrometry for Metabolites of Drugs and Drug Candidates

Dahal, Upendra P.; Jones, Jeffrey P.; Davis, John A.; Rock, Dan A.

doi:10.1124/dmd.111.040865

Cited by 48 publications

(66 citation statements)

References 24 publications

(32 reference statements)

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“…Underlying assumption is that either the UV-absorption (when using UV) or the ionization efficiency (in LC/MS/MS) of the metabolite(s) is similar to the parent NME. Both the assumptions warrant cautious evaluation (Dahal et al, 2011) depending on the nature of the biotransformation of the NME.…”

Section: General Guidelines For Enzyme Reaction Phenotypingmentioning

confidence: 99%

Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions--an Industry Perspective

Bohnert¹,

Patel²,

Templeton³

et al. 2016

Drug Metabolism and Disposition

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Under the guidance of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), scientists from 20 pharmaceutical companies formed a Victim Drug-Drug Interactions Working Group. This working group has conducted a review of the literature and the practices of each company on the approaches to clearance pathway identification (f CL ), estimation of fractional contribution of metabolizing enzyme toward metabolism (f m ), along with modeling and simulation-aided strategy in predicting the victim drug-drug interaction (DDI) liability due to modulation of drug metabolizing enzymes. Presented in this perspective are the recommendations from this working group on: 1) strategic and experimental approaches to identify f CL and f m , 2) whether those assessments may be quantitative for certain enzymes (e.g., cytochrome P450, P450, and limited uridine diphosphoglucuronosyltransferase, UGT enzymes) or qualitative (for most of other drug metabolism enzymes), and the impact due to the lack of quantitative information on the latter. Multiple decision trees are presented with stepwise approaches to identify specific enzymes that are involved in the metabolism of a given drug and to aid the prediction and risk assessment of drug as a victim in DDI. Modeling and simulation approaches are also discussed to better predict DDI risk in humans. Variability and parameter sensitivity analysis were emphasized when applying modeling and simulation to capture the differences within the population used and to characterize the parameters that have the most influence on the prediction outcome.

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Section: General Guidelines For Enzyme Reaction Phenotypingmentioning

confidence: 99%

Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions--an Industry Perspective

Bohnert¹,

Patel²,

Templeton³

et al. 2016

Drug Metabolism and Disposition

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“…For phase I metabolites which are structurally similar to the parent, the FS MS response is likely to be different by up to an order of magnitude of each other [17]. For phase I and II metabolites which are significantly different to that of the parent, such as cleavage of large functionalities or conjugations, the difference in MS response is likely to be even greater.…”

Section: Sample Preparation and Acquisition Strategymentioning

confidence: 96%

Introduction of A Routine Quan/Qual Approach Into Research DMPK: Experiences and Evolving Strategies

2014

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After graduating with an Oceanography degree from Swansea University, Lloyd has spent over 20 years in the field of bioanalysis and metabolite profiling. He started his career in large pharma at Wyeth UK, where he was involved in setting up the first GC and LC-MS/MS systems for both QC and early DMPK assays, employing EI/CI, thermospray, and the then new electrospray ionization techniques. Lloyd then joined Celltech, now UCB, where he is primarily tasked with metabolite profiling by LC-MS and NMR to support both early research projects and late-stage clinical studies. The application of liquid chromatography high-resolution mass spectrometry for simultaneous quantitative and qualitative (quan/qual) analysis has gained momentum across a range of different scientific arenas in recent years. The ability to acquire high quality quantitative data, whilst also capturing qualitative data for either parallel or retrospective analysis, is a powerful resource, especially in view of ever-reducing cycle times, laboratory space and budgets. The quan/qual approach employing a Q-Exactive™ Orbitrap high-resolution mass spectrometer has been successfully introduced into UCB's research DMPK department. This article describes our experiences in introducing quan/qual, issues that we discovered in establishing this new working paradigm, the evolution of the strategy and its future potential.

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“…Furthermore, LC gradients affect the MS response, as compounds with different retention times are sprayed into the mass spectrometer in different solvent compositions [6]. Using nanospray ionization (NSI) [5,6,8,9] or captive spray ionization (CSI)-LC-MS [10,11] reduces differences in the ionization efficiency between drugs and their metabolites, but these techniques are currently not robust enough to be a strong option in post-mortem toxicology.…”

Section: Introductionmentioning

confidence: 99%

Concurrent estimation of metabolite concentrations along with parent drug quantification in post-mortem blood

Viinamäki

Ojanperä

2016

Forensic Science International

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There is a constant demand for the quantification of drug metabolites within post-mortem toxicology. Especially electrospray ionization-mass spectrometry techniques necessitate that calibration is carried out using primary reference standards due to the non-uniform ionization efficiency between parent drugs and their metabolites. As reference standards for metabolites are not readily available and their costs are high, alternative methods for immediate quantification are required. In this study, ultra-high performance liquid chromatography coupled with photodiode array detection and corona charged aerosol detection was utilized for the concurrent quantification of 23 drug metabolites using the corresponding parent drug for calibration. Based on this secondary calibration, the quantitative results for the N-demethylated metabolites by each detector were similar to those obtained by the ordinary calibration using reference standards. For O-demethylated metabolites, the differences in detector response caused somewhat larger biases using the secondary calibration. Using the validated secondary calibration, the blood sample data gathered from 633 post-mortem cases was retrospectively re-processed to discover the combined metabolite-parent concentrations and metabolite to parent ratios for six toxicologically relevant drugs. These results, representing all causes of death, were compared to published data from therapeutic drug monitoring and post-mortem toxicology.

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Small Molecule Quantification by Liquid Chromatography-Mass Spectrometry for Metabolites of Drugs and Drug Candidates

Cited by 48 publications

References 24 publications

Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions--an Industry Perspective

Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions--an Industry Perspective

Introduction of A Routine Quan/Qual Approach Into Research DMPK: Experiences and Evolving Strategies

Concurrent estimation of metabolite concentrations along with parent drug quantification in post-mortem blood

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