In:
Rapid Communications in Mass Spectrometry, Wiley, Vol. 15, No. 8 ( 2001-04-30), p. 629-636
Abstract:
A strategy for the sensitive and reliable quantitative determination of non‐polar neutral compounds in biological matrices by liquid chromatography/electrospray ionization tandem mass spectrometry is described in the context of assay development for TS‐962, a novel acyl‐CoA:cholesterol acyltransferase (ACAT) inhibitor, in rabbit aorta and liver tissues. The electrospray ionization (ESI) mass spectrum of this compound with a mobile phase of water/acetonitrile did not give abundant [M + H] + ions, but did give alkali metal cation adducts such as [M + Na] + , [M + CH 3 CN + Na] + and [M + K] + ions. The cationized species are acknowledged as unsuitable precursor ions for selected reaction monitoring (SRM) for various reasons, such as difficulty in obtaining characteristic product ions in low‐energy collision‐induced dissociation, and irreproducibility of the adduct‐ion intensities. To overcome 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 decrease of the undesirable adduct formation and significant enhancement of [M + H] + ion intensity. An attempt was then made to prevent the matrix effect by employing a column‐switching system, which allowed direct injection of a large volume of 2‐propanolic tissue homogenate (950 µL) followed by sufficient clean‐up, separation, and ESI‐SRM on‐line. This enabled development of a sensitive and reliable assay method for TS‐962 in rabbit aorta and liver tissues in the concentration range of 5–500 ng/g wet tissue using a 25‐mg 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 is also presented. Results showed that TS‐962 is well distributed to both the thoracic and abdominal aorta tissues, at levels higher than the 50% inhibitory concentration value of this compound for microsomal ACAT activity from rabbit aorta. Copyright © 2001 John Wiley & Sons, Ltd.
Type of Medium:
Online Resource
ISSN:
0951-4198
,
1097-0231
Language:
English
Publisher:
Wiley
Publication Date:
2001
detail.hit.zdb_id:
2002158-6
detail.hit.zdb_id:
58731-X
SSG:
11
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