A strategy for quantitative bioanalysis of non-polar neutral compounds by liquid chromatography/electrospray ionization tandem mass spectrometry: determination of TS-962, a novel acyl-CoA : cholesterol acyltransferase inhibitor, in rabbit aorta and liver tissues

Citation
J. Yamaguchi et al., A strategy for quantitative bioanalysis of non-polar neutral compounds by liquid chromatography/electrospray ionization tandem mass spectrometry: determination of TS-962, a novel acyl-CoA : cholesterol acyltransferase inhibitor, in rabbit aorta and liver tissues, RAP C MASS, 15(8), 2001, pp. 629-636
Citations number
19
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Spectroscopy /Instrumentation/Analytical Sciences
Journal title
RAPID COMMUNICATIONS IN MASS SPECTROMETRY
ISSN journal
0951-4198 → ACNP
Volume
15
Issue
8
Year of publication
2001
Pages
629 - 636
Database
ISI
SICI code
0951-4198(2001)15:8<629:ASFQBO>2.0.ZU;2-3
Abstract
A strategy for the sensitive and reliable quantitative determination of non -polar neutral compounds in biological matrices by liquid chromatography/el ectrospray ionization tandem mass spectrometry is described in the context of assay development for TS-962, a novel acyl-CoA:cholesterol acyltransfera se (ACAT) inhibitor, in rabbit aorta and liver tissues. The electrospray io nization (ESI) mass spectrum of this compound with a mobile phase of water/ acetonitrile did not give abundant [M + H](+) ions, but did give alkali met al cation adducts such as [M + Na](+), [M + CH3CN + Na](+) and [M + K](+) i ons. The cationized species are acknowledged as unsuitable precursor ions f or selected reaction monitoring (SRM) for various reasons, such as difficul ty in obtaining characteristic product ions in low-energy collision-induced dissociation, and irreproducibility of the adduct-ion intensities. To over come this problem, a solution of 3.4 mM trifluoroacetic acid in 2-propanol was added to the mobile phase as a postcolumn additive, resulting in a decr ease of the undesirable adduct formation and significant enhancement of [M + H](+) ion intensity. An attempt was then made to prevent the matrix effec t by employing a column-switching system, which allowed direct injection of a large volume of 2-propanolic tissue homogenate (950 muL) followed by suf ficient clean-up, separation, and ESI-SRM online. This enabled development of a sensitive and reliable assay method for TS-962 in rabbit aorta and liv er tissues in the concentration range of 5-500 ng/g wet tissue using a 25-m g aliquot of tissue sample. Application of this method to the determination of aortic TS-962 levels at 24 h after repeated oral administration of this compound (3 mg/kg) once a day for 12 weeks to 1% cholesterol-fed rabbits i s also presented. Results showed that TS-962 is well distributed to both th e thoracic and abdominal aorta tissues, at levels higher than the 50% inhib itory concentration value of this compound for microsomal ACAT activity fro m rabbit aorta. Copyright (C) 2001 John Wiley & Sons, Ltd.