Evaluation of relative LC/MS response of metabolites to parent drug in LC/nanospray ionization mass spectrometry: potential implications in MIST assessment

Schadt, Heiko S.; Chen, Linzhi; Bischoff, Daniel

doi:10.1002/jms.2018

Cited by 23 publications

(19 citation statements)

References 13 publications

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“…Differences in ionization efficiency of compounds with different physicochemical characteristics are in general reduced by the application of chip-based NSI (Hop et al, 2005;Hop, 2006;Valaskovic et al, 2006;Wickremsinhe et al, 2006;Ramanathan et al, 2007). Recently, the accuracy of nano-electrospray ionization MS response of drug compounds and their respective metabolites from biological matrices compared with accurate radiometric quantification was evaluated, and it has been demonstrated that nanoelectrospray mass spectrometry can be used for semiquantitation of metabolites (Schadt et al, 2011). For LESA-MS, the accuracy of semiquantification results was expected to be even higher, because no chromatographic separation was used, and therefore different LC mobile phase compositions and matrix effects could not contribute to variations in MS response.…”

Section: Discussionmentioning

confidence: 99%

Investigation of Figopitant and Its Metabolites in Rat Tissue by Combining Whole-Body Autoradiography with Liquid Extraction Surface Analysis Mass Spectrometry

Schadt

Kallbach²,

Almeida

et al. 2011

Drug Metab Dispos

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ABSTRACT:This article describes the combination of whole-body autoradiography with liquid extraction surface analysis (LESA) and mass spectrometry (MS) to study the distribution of the tachykinin neurokinin-1 antagonist figopitant and its metabolites in tissue sections of rats after intravenous administration of 5.0 mg/kg figopitant. An overview of autoradiography results is presented together with mass spectrometry identification and semiquantification of parent drug and its metabolites based on LESA-MS. The quality and accuracy of data generated by LESA-MS were assessed in comparison with classic tissue extraction, sample cleanup, and high-performance liquid chromatography analysis. The parent drug and the N-dealkylated metabolite M474(1) (BIIF 1148) in varying ratios were the predominant compounds in all tissues investigated. In addition, several metabolites formed by oxygenation, dealkylation, and a combination of oxygenation and dealkylation were identified. In summary, the LESA-MS technique was shown to be a powerful tool for identification and semiquantification of figopitant and its metabolites in different tissues and was complementary to quantitative whole-body autoradiography for studying the distribution. IntroductionQuantitative whole-body autoradiography (QWBA) is the imaging method of choice to investigate the distribution of drug-related radioactivity in all organs and tissues of an intact organism, such as an animal carcass. With this technique, information on the concentration of the entire drug-related radioactivity is gained. However, the actual molecular entity-parent compound or metabolites-and their respective proportions of the radioactivity remains unknown. The conventional approach to identify and quantify parent drug and metabolites in tissues is the preparation of organ homogenates and sample analysis by liquid chromatography combined with radiodetection and tandem mass spectrometry (MS/MS). However, this approach is labor-intensive, and some tissues (e.g., salivary glands) and tissue substructures (e.g., renal inner and outer medulla) can be difficult or even impossible to sample and extract. Surface sampling methods such as desorption electrospray ionization, laser desorption ionization, direct analyses in real time, or matrix-assisted laser desorption ionization can speed up analysis time and cut overall costs compared with classic tissue extraction and enable spatial resolution of different anatomical substructures within a given organ (Reyzer et al., 2003).Recently, a fully automated liquid extraction-based surface sampling method for mass spectrometry (MS) analyses of drugs and metabolites in thin tissue sections has been described (Van Berkel and Kertesz, 2009;Kertesz and Van Berkel, 2010). This liquid extraction surface analysis (LESA) method uses a liquid microjunction probe to extract the analytes directly from the surface followed by automated nano-electrospray analysis. Direct surface sampling methods deal with high sample complexity, because no chromatographic separation ...

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Section: Discussionmentioning

confidence: 99%

Investigation of Figopitant and Its Metabolites in Rat Tissue by Combining Whole-Body Autoradiography with Liquid Extraction Surface Analysis Mass Spectrometry

Schadt

Kallbach²,

Almeida

et al. 2011

Drug Metab Dispos

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“…Bioanalysis (2014) 6 (6) sizes. This, once again, could be a result of different resolution of undetected matrix components present in the final extracts.…”

Section: Research Article | Danaceau Yu Chambers and Fountainmentioning

confidence: 99%

“…Schadt et al compared the accuracy of determining relative abundance of metabolites (as percentage of parent) by MS peak areas and by radioactivity. Their data indicated that for the majority of metabolites, determination of abundance of metabolites (as percentage of parent) by MS peak areas were within threefold from that determined by radioactivity [6]. Therefore, MS peak areas of metabolites can provide an initial estimation of their relative abundance (i.e., likely to be a major or a minor metabolite).…”

mentioning

confidence: 94%

“…One important caveat is that the MS peak areas may not always represent the actual concentrations of the parent and metabolites due to potential differences in MS ionization efficiency. It is well known that metabolism often results in structural changes that may change mass spectrometric responses of metabolites [6]. Schadt et al compared the accuracy of determining relative abundance of metabolites (as percentage of parent) by MS peak areas and by radioactivity.…”

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confidence: 99%

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Matrix Effects in Metabolite Quantification for Mist Assessment: The Impact of Phospholipid Removal and HPLC Column Particle Size

Danaceau

Chambers

et al. 2014

Bioanalysis

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“…The possible explanations of this observation could be: 1) Non-cytochrome P450-dependent drug metabolism may lead to an overestimation of glucuronidation rate for drugs that could be metabolized by non-P450 enzymes; 2) different ionization efficiency between acyl glucuronide isomers and parent drug. Ionization efficiency of parent drug and metabolites has been extensively studied (Schadt et al, 2011), revealing that the MS signal intensity could vary remarkably, especially in cases of substantial structural differences between the parent drug and the metabolites. It is thus possible that the glucuronidation rate could not be properly assessed in absence of an analytical standard.…”

Section: Fda 2008mentioning

confidence: 99%

A New Rapid In Vitro Assay for Assessing Reactivity of Acyl Glucuronides

Zhong

Jones

et al. 2015

Drug Metab Dispos

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Idiosyncratic drug toxicity is a major challenge for the pharmaceutical industry since complex and multifactorial steps are involved, the dose-dependency is unclear, and its occurrence is not reliably predictable. Whereas the exact mechanisms leading to idiosyncratic toxicity remain elusive in many cases, there are often hints at the involvement of reactive metabolites, such as acyl glucuronides formed by conjugation of carboxylic acids with glucuronic acid. Because the patient-related susceptibilities leading to idiosyncratic toxicity are not sufficiently understood, the best option for the pharmaceutical industry is to minimize drug-related risk factors such as potential acyl glucuronide formation. Here, we describe a rapid in vitro assay for the assessment of the reactivity of acyl glucuronides, on the basis of acyl glucuronide migration, that can support the selection of low-risk drug candidates in the drug discovery phase. Twenty marketed compounds with a wide range of half-lives were tested, their acyl glucuronide migration rates were determined and compared with the half-lives of the respective acyl glucuronides. Ranking of acyl glucuronide stability using this method compared well with the results from existing methodologies. With this method, migration rates >20% would indicate higher risk of reactivity. This simpler approach using the acyl glucuronide migration rate is not dependent on authentic standards, therefore eliminating the requirement for either lengthy chemical synthesis or in vitro biosynthesis and purification of the 1-O-b-glucuronide. This methodology provides a rapid in vitro assay to assess acyl glucuronide stability and reactivity that is well suited for use early in the drug discovery phase.

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Evaluation of relative LC/MS response of metabolites to parent drug in LC/nanospray ionization mass spectrometry: potential implications in MIST assessment

Cited by 23 publications

References 13 publications

Investigation of Figopitant and Its Metabolites in Rat Tissue by Combining Whole-Body Autoradiography with Liquid Extraction Surface Analysis Mass Spectrometry

Investigation of Figopitant and Its Metabolites in Rat Tissue by Combining Whole-Body Autoradiography with Liquid Extraction Surface Analysis Mass Spectrometry

Matrix Effects in Metabolite Quantification for Mist Assessment: The Impact of Phospholipid Removal and HPLC Column Particle Size

A New Rapid In Vitro Assay for Assessing Reactivity of Acyl Glucuronides

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