High‐Resolution Mass Spectrometry and Drug Metabolite Identification

Mortishire‐Smith, Russell J.; Zhang, Haiying; Bateman, Kevin P.

doi:10.1002/9780470929278.ch13

Cited by 5 publications

(3 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Traditionally, metabolite characterization has relied heavily on liquid chromatography–mass spectrometry (LC-MS) techniques for sensitivity reasons. With the advancement of high resolution (HR)-MS/MS capabilities, investigators can define the metabolically modified region(s) of the molecule and propose likely metabolite structures based on the molecular weight change and MS/MS fragmentation pattern. − …”

Section: Introductionmentioning

confidence: 99%

Definitive Metabolite Identification Coupled with Automated Ligand Identification System (ALIS) Technology: A Novel Approach to Uncover Structure–Activity Relationships and Guide Drug Design in a Factor IXa Inhibitor Program

et al. 2016

View full text Add to dashboard Cite

A potent and selective Factor IXa (FIXa) inhibitor was subjected to a series of liver microsomal incubations, which generated a number of metabolites. Using automated ligand identification system-affinity selection (ALIS-AS) methodology, metabolites in the incubation mixture were prioritized by their binding affinities to the FIXa protein. Microgram quantities of the metabolites of interest were then isolated through microisolation analytical capabilities, and structurally characterized using MicroCryoProbe heteronuclear 2D NMR techniques. The isolated metabolites recovered from the NMR experiments were then submitted directly to an in vitro FIXa enzymatic assay. The order of the metabolites' binding affinity to the Factor IXa protein from the ALIS assay was completely consistent with the enzymatic assay results. This work showcases an innovative and efficient approach to uncover structure-activity relationships (SARs) and guide drug design via microisolation-structural characterization and ALIS capabilities.

show abstract

Section: Introductionmentioning

confidence: 99%

Definitive Metabolite Identification Coupled with Automated Ligand Identification System (ALIS) Technology: A Novel Approach to Uncover Structure–Activity Relationships and Guide Drug Design in a Factor IXa Inhibitor Program

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Resolution is a well-defined term in MS. As stated in the definitive article by Murray et al, mass resolution can be defined in a mass spectrum as 'the observed m/z value divided by the smallest difference Δ(m/z) for two ions that can be separated: (m/z)/ Δ(m/z)' [1]. As a general rule, a mass spectrometer with mass resolution of 10,000 or higher is defined as high resolution [2,3]. So, high-resolution mass spectrometers include TOF MS systems as well as Orbitrap MS systems, while quadrupole systems would be called nominal mass resolution systems.…”

mentioning

confidence: 99%

“…The term is mass accuracy. Mass accuracy refers to how accurately one can measure the mass of the analyte as compared with its exact mass [2]. Exact mass is the 'calculated mass of an ion or molecule with specified isotopic composition' [1].…”

mentioning

confidence: 99%

HRMS or Hrams?

Ramanathan

Korfmacher

2016

Bioanalysis

View full text Add to dashboard Cite

In vivo drug metabolite identification in preclinical ADME studies by means of UPLC/TWIMS/high resolution-QTOF MS^E and control comparison: cost and benefit of vehicle-dosed control samples

et al. 2016

View full text Add to dashboard Cite

1. Liquid chromatography (LC)-high resolution mass spectrometry (HRMS) techniques proved to be well suited for the identification of predicted and unexpected drug metabolites in complex biological matrices. 2. To efficiently discriminate between drug-related and endogenous matrix compounds, however, sophisticated postacquisition data mining tools, such as control comparison techniques are needed. For preclinical absorption, distribution, metabolism and excretion (ADME) studies that usually lack a placebo-dosed control group, the question arises how high-quality control data can be yielded using only a minimum number of control animals. 3. In the present study, the combination of LC-traveling wave ion mobility separation (TWIMS)-HRMS(E) and multivariate data analysis was used to study the polymer patterns of the frequently used formulation constituents polyethylene glycol 400 and polysorbate 80 in rat plasma and urine after oral and intravenous administration, respectively. 4. Complex peak patterns of both constituents were identified underlining the general importance of a vehicle-dosed control group in ADME studies for control comparison. Furthermore, the detailed analysis of administration route, blood sampling time and gender influences on both vehicle peak pattern as well as endogenous matrix background revealed that high-quality control data is obtained when (i) control animals receive an intravenous dose of the vehicle, (ii) the blood sampling time point is the same for analyte and control sample and (iii) analyte and control samples of the same gender are compared.

show abstract

High‐Resolution Mass Spectrometry and Drug Metabolite Identification

Cited by 5 publications

References 87 publications

Definitive Metabolite Identification Coupled with Automated Ligand Identification System (ALIS) Technology: A Novel Approach to Uncover Structure–Activity Relationships and Guide Drug Design in a Factor IXa Inhibitor Program

Definitive Metabolite Identification Coupled with Automated Ligand Identification System (ALIS) Technology: A Novel Approach to Uncover Structure–Activity Relationships and Guide Drug Design in a Factor IXa Inhibitor Program

HRMS or Hrams?

In vivo drug metabolite identification in preclinical ADME studies by means of UPLC/TWIMS/high resolution-QTOF MS^E and control comparison: cost and benefit of vehicle-dosed control samples

Contact Info

Product

Resources

About

High‐Resolution Mass Spectrometry and Drug Metabolite Identification

Cited by 5 publications

References 87 publications

Definitive Metabolite Identification Coupled with Automated Ligand Identification System (ALIS) Technology: A Novel Approach to Uncover Structure–Activity Relationships and Guide Drug Design in a Factor IXa Inhibitor Program

Definitive Metabolite Identification Coupled with Automated Ligand Identification System (ALIS) Technology: A Novel Approach to Uncover Structure–Activity Relationships and Guide Drug Design in a Factor IXa Inhibitor Program

HRMS or Hrams?

In vivo drug metabolite identification in preclinical ADME studies by means of UPLC/TWIMS/high resolution-QTOF MSE and control comparison: cost and benefit of vehicle-dosed control samples

Contact Info

Product

Resources

About

In vivo drug metabolite identification in preclinical ADME studies by means of UPLC/TWIMS/high resolution-QTOF MS^E and control comparison: cost and benefit of vehicle-dosed control samples