title: Liquid chromatography-tandem mass spectrometric assay for the PI3K/mTOR inhibitor GSK2126458 in mouse plasma and tumor homogenate.
abstract: A quantitative bioanalytical liquid chromatography-tandem mass spectrometric (LC-MS/MS) assay for GSK2126458, a dual PI3K/mTOR inhibitor, was developed and validated. Plasma and tumor homogenate samples were pre-treated using protein precipitation with acetonitrile containing dabrafenib as internal standard. After dilution with water, the extract was directly injected into the reversed-phase liquid chromatographic system. The eluate was transferred into the electrospray interface with positive ionization and compounds were detected in the selected reaction monitoring mode of a triple quadrupole mass spectrometer. The assay was completely validated for plasma in a 4-4000 ng/ml calibration range with r(2)=0.9996±0.0003 using double logarithmic calibration (n=5). Within-run precisions (n=6) were 2.0-5.3% and between-run (3 runs; n=18) precisions 2.7-5.8%. Accuracies were between 101 and 105% for the whole calibration range. The drug was sufficiently stable under all relevant analytical conditions. Finally, the assay was successfully applied to determine plasma and tumor drug levels after oral administration of GSK2126458 to mice with AMC711T neuroblastoma xenografts.
authors: Amsterdam Medical Center, University of Amsterdam, Department of Oncogenomics, Meibergdreef 15, PO Box 22700, 1105 AZ Amsterdam, The Netherlands.
authors: M Emmy M
authors: ME
authors: Dolman
authors: Amsterdam Medical Center, University of Amsterdam, Department of Oncogenomics, Meibergdreef 15, PO Box 22700, 1105 AZ Amsterdam, The Netherlands.
authors: Ellen M
authors: EM
authors: Westerhout
authors: Amsterdam Medical Center, University of Amsterdam, Department of Oncogenomics, Meibergdreef 15, PO Box 22700, 1105 AZ Amsterdam, The Netherlands.
authors: Mohamed
authors: M
authors: Hamdi
authors: Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical Pharmacology, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands; The Netherlands Cancer Institute, Department of Clinical Pharmacology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors: Jan H M
authors: JH
authors: Schellens
authors: Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical Pharmacology, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands; The Netherlands Cancer Institute, Department of Clinical Pharmacology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; Slotervaart Hospital, Department of Pharmacy & Pharmacology, Louwesweg 6, 1066 EC Amsterdam, The Netherlands.
authors: Jos H
authors: JH
authors: Beijnen
authors: Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical Pharmacology, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands. Electronic address: R.W.Sparidans@uu.nl.
authors: Rolf W
authors: RW
authors: Sparidans
mesh_terms: D000818:Animals; D002138:Calibration; D002853:Chromatography, Liquid / Q000379:methods; D005260:Female; D051379:Mice; D009369:Neoplasms / Q000737:chemistry*; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010949:Plasma / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000097:blood* / Q000737:chemistry / Q000494:pharmacology; D011724:Pyridazines; D011804:Quinolines / Q000097:blood* / Q000737:chemistry* / Q000494:pharmacology; D015203:Reproducibility of Results; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D013449:Sulfonamides / Q000097:blood* / Q000737:chemistry* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D053719:Tandem Mass Spectrometry / Q000379:methods; D000096926:Benzenesulfonamides
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011804:Quinolines; D013449:Sulfonamides; D058570:TOR Serine-Threonine Kinases; C561454:omipalisib; D000096926:Benzenesulfonamides
keywords: GSK2126458; LC-MS/MS; Mouse; Plasma; Tumor homogenate