Determination of the gamma-secretase inhibitor MK-0752 in human plasma by online extraction and electrospray tandem mass spectrometry (HTLC-ESI-MS/MS).
A sensitive and rapid HTLC-ESI-MS/MS method with an advanced online sample preparation was developed for determination of the gamma-secretase inhibitor MK-0752 in human plasma using an internal standard. Plasma samples (100 microL) were diluted and injected directly onto an online extraction column (Cohesive Cyclone MAX 0.5 mm x 50 mm, > 30 microm), the sample matrix was washed out with an aqueous solution, and retained analytes were eluted out and transferred directly to the analytical column (Phenomenex Gemini 3 micron C18 110A, 50 mm x 2.0 mm at 50 degrees C) for separation using a gradient mobile phase. The eluted analytes were then detected on an API-3000 LC-MS/MS System with ESI and a negative multiple reaction monitoring mode. The monitored ion transitions were m/z 441-->175 for MK-0752 and 496-->175 for the internal standard. Online extraction recoveries were 81%. The method was validated and was linear in the range of 0.05-50 microg/mL. Within-day and between-day precisions were<8.6%, and accuracies were 0.7 and 7.1%. This method was applied to the measurement of plasma MK-0752 levels in a Phase I study of pediatric patients with recurrent or refractory brain tumors.
Bai
Feng
F
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Tagen
Michael
M
Colotta
Courtney
C
Miller
Laura
L
Fouladi
Maryam
M
Stewart
Clinton F
CF
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D001555:Benzene Derivatives; D001932:Brain Neoplasms / Q000188:drug therapy; D002648:Child; D002853:Chromatography, Liquid; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000097:blood* / Q000302:isolation & purification; D006801:Humans; D016014:Linear Models; D011422:Propionates / Q000008:administration & dosage / Q000097:blood* / Q000302:isolation & purification; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*; D013450:Sulfones / Q000008:administration & dosage / Q000097:blood* / Q000302:isolation & purification; D053719:Tandem Mass Spectrometry
C554093:3-(4-((4-chlorophenyl)sulfonyl)-4-(2,5-difluorophenyl)cyclohexyl)propanoic acid; D001555:Benzene Derivatives; D004791:Enzyme Inhibitors; D011422:Propionates; D013450:Sulfones; D053829:Amyloid Precursor Protein Secretases