Simultaneously quantifying parent drugs and screening for metabolites in plasma pharmacokinetic samples using selected reaction monitoring information-dependent acquisition on a QTrap instrument

Bioanalytical support of plasma pharmacokinetic (PK) studies for drug discovery programs primarily involves the quantitative analysis of dosed compounds using liquid chromatography/atmospheric pressure ionization tandem mass spectrometry (LC/MS/MS) operated in selected reaction monitoring (SRM) mode...

Full description

Saved in:

Bibliographic Details
Published in:	Rapid communications in mass spectrometry Vol. 19; no. 14; pp. 1943 - 1950
Main Authors:	Li, Austin C., Alton, Dennis, Bryant, Matthew S., Shou, Wilson Z.
Format:	Journal Article
Language:	English
Published:	Chichester, UK John Wiley & Sons, Ltd 01-01-2005
Subjects:	Animals Calibration Chromatography, Liquid - methods Drug Evaluation, Preclinical - instrumentation Haplorhini Pharmaceutical Preparations - blood Pharmacokinetics Spectrometry, Mass, Electrospray Ionization - methods
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Bioanalytical support of plasma pharmacokinetic (PK) studies for drug discovery programs primarily involves the quantitative analysis of dosed compounds using liquid chromatography/atmospheric pressure ionization tandem mass spectrometry (LC/MS/MS) operated in selected reaction monitoring (SRM) mode. However, there is a growing need for information on the metabolism of new chemical entities (NCEs), in addition to the time‐concentration profiles from these studies. In this paper, we present a novel approach to not only quantify parent drugs with SRM, but also simultaneously screen for metabolites using a hybrid triple quadrupole/linear ion trap (QqQLIT) instrument. This was achieved by incorporating both the conventional SRM‐only acquisition of parent compounds and the SRM‐triggered information‐dependent acquisition (IDA) of potential metabolites within the same scan cycle during the same LC/MS/MS run. Two test compounds were used to demonstrate the applicability of this approach. Plasma samples from PK studies were processed by simple protein precipitation and the supernatant was diluted with water before injection. The fast scanning capability of the linear ion trap allowed for the information‐dependent acquisition of metabolite MS/MS spectra (< 1 s/scan), in addition to the collection of adequate data points for SRM‐only channels. The MS/MS spectra obtained from potential metabolites in post‐dose samples correlated well with the spectra of the parent compounds studied, therefore providing additional confirmatory structure information without the need for repetitive analyses. Relative quantitative time‐concentration profiles of identified metabolites were also obtained. Furthermore, this articulated SRM + SRM‐IDA approach generated equivalent quantitative results for parent compounds to those obtained by conventional SRM‐only analysis. This approach has been successfully used to support discovery PK screening programs. Copyright © 2005 John Wiley & Sons, Ltd.
Bibliography:	ArticleID:RCM2008 istex:CF623F137463C85142C07A461FE23DCAF8FD31A1 ark:/67375/WNG-S7652R54-H ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0951-4198 1097-0231
DOI:	10.1002/rcm.2008