Metabolite Interference in Pharmacokinetic Studies

Moghaddam, Mehran F.; Fan, Jui-Hsiang; Tang, Yang; Khatsenko, Oleg G.; Katz, Jason C.; Shirley, Michael A.

doi:10.2174/187231207783221475

Cited by 1 publication

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“…Other structural clues include carboxylic acid16 or phenol17 groups, which can be problematic due to their potential metabolic conversion into thermally unstable glucuronide conjugates. Many other potentially problematic structural motifs have been reported 6–11, 13, 18–25, 29, 31–39…”

Section: Resultsmentioning

confidence: 99%

“…Isomerization is a facile mechanism by which this type of conversion can occur 5. Reported examples of in vivo isomerization include E to Z inter‐conversion of a methyloxime‐based carbon–nitrogen double bond6 and epimerization of an alcohol group on a cyclohexane moiety 7–11. Isoxazole‐ring‐containing compounds have been shown in certain cases to undergo enzyme‐mediated ring opening to form isobaric metabolites 12, 13.…”

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confidence: 99%

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Identifying and overcoming bioanalytical challenges associated with chlorine-containing dehydrogenation metabolites

Furlong

Wujcik

et al. 2010

Rapid Commun. Mass Spectrom.

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Liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS) is a widely utilized analytical tool for quantifying small molecules in complex biological matrices. In certain situations the mass-selection capabilities of the tandem mass spectrometer may be insufficient to discriminate between the analyte of interest and its metabolites, particularly those metabolites that are isobaric with the analyte. One scenario by which isobaric interference may occur is the metabolism of a chlorine- or bromine-containing small molecule to a metabolite with the concomitant loss of 2 Da. This report describes the detection and characterization of two distinct dehydrogenation [M-2] metabolites during LC/MS/MS quantification of a chlorinated small molecule in rat plasma samples derived from a toxicokinetic study. The potential isotope-related impact of these metabolites on quantification of the parent compound was assessed. Several alternate precursor ion and product ion combinations were evaluated and shown to minimize the quantitative impact of the interfering metabolites without having to rely on their stringent chromatographic resolution from the parent compound. These results indicate that when quantifying chlorine- or bromine-containing small molecules from in vivo samples or in vitro metabolic incubations: (1) efforts to detect potential dehydrogenation metabolites should be undertaken and (2) if such metabolites are detected, the judicious choice of alternate multiple-reaction monitoring (MRM) transitions can limit their impact on quantification of the parent molecule without the need for robust chromatographic resolution.

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