Document Detail


Determination of a novel gamma-secretase inhibitor in human plasma and cerebrospinal fluid using automated 96 well solid phase extraction and liquid chromatography/tandem mass spectrometry.
MedLine Citation:
PMID:  18249589     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A method for determination of a gamma-secretase inhibitor, cis-3-[4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]propanoic acid (A), in human plasma and cerebrospinal fluid (CSF) has been developed to support the clinical investigation of compound A for its potential treatment of Alzheimer's disease. The method is based on HPLC with atmospheric pressure chemical ionization tandem mass spectrometric detection (APCI-MS/MS) in the negative ionization mode using a heated nebulizer interface. The addition of phosphoric acid at the ratio of 10-30microL per milliliter of human plasma or CSF was required during clinical sample collection to stabilize an acylglucuronide metabolite (C), which was potentially present in human plasma and CSF. Tween 20 (10% solution) was added at the ratio of 20microL per milliliter of CSF during CSF sample collection to prevent the loss of compound A during the storage of clinical samples. The compound A and its analog internal standard (B) in treated plasma or CSF were isolated from human plasma or CSF using solid phase extraction (SPE) in the 96 well format. The isolated analyte and internal standard were chromatographed on a Phenomenex Synergi Polar RP analytical column (50mmx3.0mm, 4microm), using a mobile phase consisting of 60/40 (v/v, %) acetonitrile/water at a flow-rate of 0.5mL/min. Tandem mass spectrometric detection was performed using a Sciex API 3000 tandem mass spectrometer operated in the multiple reaction monitoring (MRM) mode using precursor to product ion transitions of 441-->175 for A and 469-->175 for B, respectively. The assays were validated over the concentration range of 0.5-200ng/mL for human plasma and CSF. Replicate analyses (n=5) of spiked standards for both assays yielded a linear response with coefficients of variation less than 7% and accuracy within 5% of the nominal concentrations. In addition, the assays were automated to improve sample throughput by utilizing a Packard Multi PROBEII automated liquid handling system and a Tom-Tec Quadra 96 system. Numerous clinical studies have been supported using these assays.
Authors:
Catherine Z Matthews; Eric J Woolf
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Publication Detail:
Type:  Journal Article     Date:  2008-01-06
Journal Detail:
Title:  Journal of chromatography. B, Analytical technologies in the biomedical and life sciences     Volume:  863     ISSN:  1570-0232     ISO Abbreviation:  J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.     Publication Date:  2008 Feb 
Date Detail:
Created Date:  2008-02-18     Completed Date:  2008-05-01     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101139554     Medline TA:  J Chromatogr B Analyt Technol Biomed Life Sci     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  36-45     Citation Subset:  IM    
Affiliation:
Department of Drug Metabolism, Sumneytown Pike, West Point, PA 19486, USA. catherine_matthews@merck.com
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MeSH Terms
Descriptor/Qualifier:
Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Autoanalysis
Chromatography, High Pressure Liquid
Cyclohexanes / analysis*,  blood
Enzyme Inhibitors / analysis*,  blood,  cerebrospinal fluid
Freezing
Glucuronides / metabolism
Humans
Indicators and Reagents
Propionic Acids / analysis*,  blood
Quality Control
Specimen Handling
Tandem Mass Spectrometry
Chemical
Reg. No./Substance:
0/Cyclohexanes; 0/Enzyme Inhibitors; 0/Glucuronides; 0/Indicators and Reagents; 0/Propionic Acids; 0/cis-3-(4-((4-chlorophenyl)sulfonyl)-4-(2,5-difluorophenyl)cyclohexyl)propanoic acid; EC 3.4.-/Amyloid Precursor Protein Secretases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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