Determination of the acylcoenzyme A cholesterol acyltransferase inhibitor 447C88 in plasma using gas chromatography-mass spectrometry and liquid chromatography atmospheric pressure chemical ionisation tandem mass spectrometry.
Two mass spectrometry-based methods are described for the determination of 447C88 (I), a novel inhibitor of acylcoenzyme A cholesterol acyltransferase (ACAT), in rat, dog and human plasma. The first method uses gas chromatography-mass spectrometry (GC-MS) with electron ionisation and selected-ion monitoring. The method employs solid-phase extraction of I from plasma and requires alkylation of I using iodoethane. The second method uses liquid chromatography-tandem mass spectrometry (LC-MS-MS) with atmospheric-pressure chemical-ionisation and selected-reaction monitoring. The LC-MS-MS method uses a simplified version of the extraction procedure used for GC-MS and does not require derivatisation of I. While both methods provide the necessary limit of quantitation of 0.5 ng/ml in human, dog and rat plasma with the required precision and accuracy, the LC-MS-MS assay offers increased sensitivity, selectivity and speed over the GC-MS assay. This allows a same day turn round of results for in excess of 100 samples, including sample preparation and data acquisition and processing.
Fraser
I J
IJ
Department of Bioanalysis and Drug Metabolism, Wellcome Research Laboratories, Beckenham, Kent, UK.
Clare
R A
RA
Pleasance
S
S
D000478:Alkylation; D000818:Animals; D002853:Chromatography, Liquid; D004285:Dogs; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D013058:Mass Spectrometry; D010671:Phenylurea Compounds / Q000097:blood* / Q000494:pharmacology; D051381:Rats; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*
C093460:447C88; D010671:Phenylurea Compounds; D002785:Sterol O-Acyltransferase