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High‐throughput analysis in drug discovery: application of liquid chromatography/ion‐trap mass spectrometry for simultaneous cassette analysis of α‐1a antagonists and their metabolites in mouse plasma
Author(s) -
Cai Zongwei,
Han Chao,
Harrelson Stephanie,
Fung Eliza,
Sinhababu Achintya K.
Publication year - 2001
Publication title -
rapid communications in mass spectrometry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.528
H-Index - 136
eISSN - 1097-0231
pISSN - 0951-4198
DOI - 10.1002/rcm.266
Subject(s) - chemistry , chromatography , in vivo , metabolite , mass spectrometry , hydroxylation , drug metabolism , pharmacokinetics , demethylation , quantitative analysis (chemistry) , liquid chromatography–mass spectrometry , tandem mass spectrometry , metabolism , pharmacology , biochemistry , medicine , microbiology and biotechnology , biology , enzyme , gene expression , gene , dna methylation
The application of liquid chromatography/ion‐trap mass spectrometry for simultaneous quantification of multiple drugs and detection of their metabolites for in vitro experiments was reported recently. In the current study, the use of these techniques was extended to in vivo pharmacokinetic (PK) studies of α‐1a antagonists. In combination with limited time‐point PK, greatly increased throughput was demonstrated for the in vivo screening and investigation of in vivo–in vitro correlation. In addition to quantitative analyses, the technique allowed simultaneous detection of major in vivo metabolites without having to reanalyze the plasma samples. The drugs were individually dosed in mice intravenously via tail vein injection and the blood samples were collected 5 min and 2 h after dosing. After the plasma samples for the different drugs had been prepared separately, they were pooled for cassette analysis. The concentrations of five test compounds in the plasma samples at 2 h ranged from 36–1062 ng/mL, whereas their 5‐min plasma levels were similar. From the same cassette analysis, major metabolites in the samples were also detected simultaneously through the interpretation of full‐scan mass spectra. The metabolite identification confirmed the results from a previous report that the major sites of metabolism are hydroxylation of the phenyl ring not bearing the alkylsulfonamide substitutent, piperidine N‐dealkylation, and N‐demethylation of the alkylsulfonamide group. Copyright © 2001 John Wiley & Sons, Ltd.