title: Simultaneous determination of nine tyrosine kinase inhibitors by 96-well solid-phase extraction and ultra performance LC/MS-MS.
abstract: BACKGROUND
  Tyrosine Kinase Inhibitors (TKIs) are a class of targeted drugs for the treatment of malignant pathologies. The metabolic profile of these drugs can result in great interindividual variability, thus therapeutic drug monitoring (TDM) is of importance. Here, a rapid and specific method for quantification of nine TKIs in plasma samples is described.
  
  
  METHODS
  Chromatography was performed on a Waters Acquity-UPLC® system with BEH C18-50*2.1 mm column, under a gradient of ammonium formate-acetonitrile. An Acquity-TQD® with electrospray ionization was used for detection. Samples were prepared by solid phase extraction (Oasis® MCX μElution) and eluate was injected in the system.
  
  
  RESULTS
  Calibration curves ranged from 10 to 5000 ng/mL for imatinib, its metabolite, nilotinib, lapatinib, erlotinib and sorafenib and from 0.1 to 200 ng/mL for dasatinib, axitinib, gefitinib and sunitinib. Peaks of each compound (retention time from 0.76 to 2.51 min) were adequately separated. The mean relative extraction recovery was in the range of 90.3-106.5% thanks to the use of stable isotopes as internal standard. There was no significant ion suppression observed at the respective TKI retention times.
  
  
  CONCLUSIONS
  This rapid, sensitive and specific UPLC/MS-MS method is able to perform simultaneous quantification of nine TKIs in human plasma and usable for routine TDM.
authors.affiliation: Department of Clinical Pharmacology and Toxicology, Pellegrin Hospital and University Victor Segalen, 33076 Bordeaux, France. stephane.bouchet@chu-bordeaux.fr
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bouchet
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Chauzit
authors.forename: Dominique
authors.initials: D
authors.lastname: Ducint
authors.forename: Nadège
authors.initials: N
authors.lastname: Castaing
authors.forename: Mireille
authors.initials: M
authors.lastname: Canal-Raffin
authors.forename: Nicholas
authors.initials: N
authors.lastname: Moore
authors.forename: Karine
authors.initials: K
authors.lastname: Titier
authors.forename: Mathieu
authors.initials: M
authors.lastname: Molimard
mesh_terms: D001774:Blood Chemical Analysis / Q000379:methods* / Q000592:standards; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D006801:Humans; D016014:Linear Models; D047428:Protein Kinase Inhibitors / Q000097:blood* / Q000302:isolation & purification* / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012015:Reference Standards; D052616:Solid Phase Extraction; D053719:Tandem Mass Spectrometry; D013997:Time Factors
chemical_list: D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases