Use of electrospray ionization and neutral loss liquid chromatography/tandem mass spectrometry in drug metabolism studies

Abstract

The application of liquid chromatography/mass spectrometry (LC/MS) and LC/MS/MS with electrospray ionization to drug metabolism studies was investigated using S 9788 and various synthesized metabolic products as model compounds to assess the response characteristics with regard to compound lipophilicity and the influence of biological matrix components. The results obtained demonstrate the versatility of the electrospray ionization technique to analyse compounds of widely varying polarity and the power of MS/MS to identify unequivocally metabolic products. These techniques offer a very rapid screening procedure that can be used to identify metabolic products and thus provide important early metabolic information that can be used in the candidate drug selection programme. These procedures were then applied to an in vivo study sample and, using neutral loss MS/MS, it was possible to detect metabolites of S 9788 directly from a crude biological matrix (bile) without prior extraction or chromatography to confirm positively the identity of five important metabolites of S 9788 in the rat.

Detection and Characterization of Metabolites in Biological Matrices Using Mass Defect Filtering of Liquid Chromatography/High Resolution Mass Spectrometry Data

“…Detection of uncommon metabolites in complex biological matrices is more challenging, and is often carried out using precursor ion (PI) or neutral loss (NL) scanning techniques on a triple quadrupole mass spectrometer (Jackson et al, 1995;Clarke et al, 2001;Kostiainen et al, 2003). The detection of conjugates (e.g., glucuronide and sulfate) can usually be accomplished with a NL analysis because these conPart of this work was presented at the 7th International ISSX Meeting, Vancouver, Canada, 29 Aug-2 Sep, 2004(Zhu et al, 2004 jugates often undergo common cleavages to generate specific neutral fragments under collision-induced dissociation conditions (Baillie and Davis, 1993;Lafaye et al, 2004).…”

“…With the availability of comprehensive metabolite databases developed from a knowledge of biotransformations, the list-dependent product ion scan has been very successful in screening for predicted metabolites, especially in vitro metabolites (Anari et al, 2004). The disadvantage of these approaches is that only predictable metabolites can be detected, and therefore, the robustness of the metabolite prediction algorithms being used becomes a critical factor.Detection of uncommon metabolites in complex biological matrices is more challenging, and is often carried out using precursor ion (PI) or neutral loss (NL) scanning techniques on a triple quadrupole mass spectrometer (Jackson et al, 1995;Clarke et al, 2001;Kostiainen et al, 2003). The detection of conjugates (e.g., glucuronide and sulfate) can usually be accomplished with a NL analysis because these conPart of this work was presented at the 7th International ISSX Meeting, Vancouver, Canada, 29 Aug-2 Sep, 2004(Zhu et al, 2004 jugates often undergo common cleavages to generate specific neutral fragments under collision-induced dissociation conditions (Baillie and Davis, 1993;Lafaye et al, 2004).…”

Rapid characterization of urinary metabolites of pibutidine hydrochloride in humans by liquid chromatography/electrospray ionization tandem mass spectrometry

“…In particular, the precursor ion and neutral loss scan techniques permit the rapid identification of drug metabolites with very little sample preparation. 6,7 However, artifacts can result from the presence of endogenous substances having fragment ions or neutral losses in common with the drug and its metabolites, and consume a significant amount of time in the drug development process. In order to overcome these limitations, we have employed an in-source CID-MS/MS approach that has also been termed 'APICID-MS/MS', 8 'quasi-MS/MS/MS' 9 or 'pseudo-MS 3 '.…”

Electrospray liquid chromatography-mass spectrometry of the leaf extract of Rhamnus prinoides

“…However, ESI-MS, is a gentle technique that has been shown to produce intact ions from many biological and chemical compounds with low or high molecular masses. Its most useful applications are in the study of supramolecular chemistry (Leize et al, 1996), in the analysis of peptides (Yates et al, 1995), oligonucleotides (Barry et al, 1995) and organic salts (Aubagnac et al, 1995), and in drug metabolism studies (Jackson et al, 1995). In our laboratory we have studied a number of glycosides using ESI-MS and have found this method to be effective and versatile.…”