Increasing the linear dynamic range in LC–MS: is it valid to use a less abundant isotopologue?

Abstract

Liquid chromatography-mass spectrometry (LC-MS) has quickly become the analytical method of choice in forensic toxicology laboratories due to its ability to detect a very wide range of compounds in a single analysis. One of the major limitations of LC-MS however, is a relatively limited linear dynamic range for quantitation. A new approach to combating this problem is to use the [ M + H] isotope mass peak for quantitation, thereby reducing saturation at the detector and extending the linear range. This is particularly useful in full-scan applications, such as quadrupole-time-of-flight (QTOF) mass spectrometry, where the isotopic mass peaks are acquired as a matter of course. Due to the variation in abundance of naturally occurring isotopes for common elements, especially C, this technique has the potential to lead to additional quantitative error. Through a review of published isotope ratio mass spectrometry data, we have assessed this potential for error and found that it is likely to be less than 2% and unlikely to be more than 4%, although this may not apply to compounds containing high numbers of nitrogen or sulphur atoms. This additional potential error must be considered before using this technique as it may not be appropriate for all applications. We have deemed it fit for purpose for our application and demonstrate the applicability of this technique to a quantitative LC-TOF method. © 2017 Commonwealth of Australia. Drug Testing and Analysis © 2017 John Wiley& Sons, Ltd.

Importance of Utilizing Natural Isotopologue Transitions in Expanding the Linear Dynamic Range of LC-MS/MS Assay for Small-Molecule Pharmacokinetic Sample Analysis – A Mini-review

“…The difference in isotopic compositions of compounds from different sources theoretically can lead to different distributions of isotopologues and inaccurate quantitative results. However, a study by Trobbiani et al 17 evaluating the variation of Acceptance criteria for linearity: 75% of the calibration standards, including the LLOQ and ULOQ, have accuracy ranging from 85 to 115% (accuracy must be within 80-120% for LLOQ). This criteria is in line with the FDA guidance.…”

Representing the Metabolome with High Fidelity: Range and Response as Quality Control Factors in LC-MS-Based Global Profiling

“…While the discussion and examples shown largely focus on advanced feature filtering, we also envision that the data provided by range and response calculations will be useful in the development of improved feature combination algorithms that go beyond the summation or averaging of features. Using detection limit information provided by the dilution series, it may become possible to extend the linear dynamic range in global profiling applications via a combination of isotopic measurements or fitting of intensity–calibration models between different ions. − An improved understanding of the underlying patterns and physical chemistry mechanisms responsible for diversity in feature response functions may avoid the loss of information by allowing a more sophisticated amalgamation of data.…”

Development and validation of an LC-MS/MS method with a broad linear dynamic range for the quantification of tivozanib in human and mouse plasma, mouse tissue homogenates, and culture medium

“…As described by Trobbiani et al the approach of using a less abundant isotopologue may introduce a quantitative error when the reference standard for calibration is from a different source to the analyte in the samples as a result of different composition regarding isotopologues, which was our case [9]. Therefore, we compared the two reference standards and the relative abundance of the different isotopes is shown in Table 2.…”