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Implications for Metabolite Quantification by Mass Spectrometry in the Absence of Authentic Standards

Hatsis, Panagiotis and Waters, Nigel and Argikar, Upendra (2017) Implications for Metabolite Quantification by Mass Spectrometry in the Absence of Authentic Standards. Drug Metabolism and Disposition.

Abstract

Quantification of metabolites by mass spectrometry in the absence of authentic reference standards or without a radiolabel is often called ‘semi-quantitative’, while acknowledging that the mass spectrometric responses are not quantitative in the same realm as UV responses. For many researchers, it is tempting to pursue this practice of semi-quantification in early drug discovery and even preclinical development, when radiolabeled ADME studies are being deferred to later stages of drug development. The caveats of quantifying metabolites based on parent drug response are explored in this investigation. A set of approximately 75 clinically relevant drugs/metabolites encompassing common biotransformation pathways, was subjected to flow injection analysis coupled with electrospray ionization mass spectrometry (ESI-MS). The results revealed a large variation in ESI response even for structurally similar parent drug/metabolite pairs. VolSurf was used to generate various 2D molecular descriptors that describe physicochemical, topological and structural properties for each drug/metabolite. The ESI response of each metabolite was normalized to that of the parent drug, to generate an ESI response factor. The molecular descriptors, along with the ESI response factors were used in univariate analyses as well as a principal components analysis to ascertain which molecular descriptors best account for the observed discrepancies in drug/metabolite ESI response.

Item Type: Article
Keywords: ESI-MS, LC/MS, biotransformation, metabolites
Date Deposited: 23 Jun 2017 00:45
Last Modified: 23 Jun 2017 00:45
URI: https://oak.novartis.com/id/eprint/31956

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