Determination of the Gamma-Secretase Inhibitor MK-0752 in Human Plasma by Online Extraction and Electrospray Tandem Mass Spectrometry (HTLC-ESI-MS/MS)

J Chromatogr B Analyt Technol Biomed Life Sci. 2010 Sep 1;878(25):2348-52. doi: 10.1016/j.jchromb.2010.07.019. Epub 2010 Jul 30.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Benzene Derivatives
  • Brain Neoplasms / drug therapy
  • Child
  • Chromatography, Liquid
  • Drug Stability
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / blood*
  • Enzyme Inhibitors / isolation & purification
  • Humans
  • Linear Models
  • Propionates / administration & dosage
  • Propionates / blood*
  • Propionates / isolation & purification
  • Reproducibility of Results
  • Sensitivity and Specificity
  • Spectrometry, Mass, Electrospray Ionization / methods*
  • Sulfones / administration & dosage
  • Sulfones / blood*
  • Sulfones / isolation & purification
  • Tandem Mass Spectrometry

Substances

  • 3-(4-((4-chlorophenyl)sulfonyl)-4-(2,5-difluorophenyl)cyclohexyl)propanoic acid
  • Benzene Derivatives
  • Enzyme Inhibitors
  • Propionates
  • Sulfones
  • Amyloid Precursor Protein Secretases