title: Liquid chromatography-tandem mass spectrometric assay for the simultaneous determination of the irreversible BTK inhibitor ibrutinib and its dihydrodiol-metabolite in plasma and its application in mouse pharmacokinetic studies.
abstract: A validated simple, fast and sensitive bio-analytical assay for ibrutinib and its dihydrodiol metabolite in human and mouse plasma was set up. Sample preparation was performed by protein precipitation, and addition of the respective deuterated internal standards, followed by LC-MS/MS analysis. Separation was performed on a 3.5 μm particle-size, bridged ethylene hybrid column with gradient elution by 0.1% v/v formic acid and acetonitrile. The full eluate was transferred to an electrospray interface in positive ionization mode, and subsequently analyzed by a triple quadrupole mass spectrometer by selected reaction monitoring. The assay was validated in a 5-5000 ng/ml calibration range. Both ibrutinib and dihydrodiol-ibrutinib were deemed stable under refrigerated or frozen storage conditions. At room temperature, ibrutinib showed a not earlier described instability, and revealed rapid degradation at 37 °C. Finally, the assay was used for a pharmacokinetic study of plasma levels in treated FVB mice.
authors.affiliation: Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical Pharmacology, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands. Electronic address: j.j.m.rood@uu.nl.
authors.forename: Johannes J M
authors.initials: JJM
authors.lastname: Rood
authors.affiliation: The Netherlands Cancer Institute, Division of Molecular Oncology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Stephanie
authors.initials: S
authors.lastname: van Hoppe
authors.affiliation: The Netherlands Cancer Institute, Division of Molecular Oncology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Schinkel
authors.affiliation: 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.forename: Jan H M
authors.initials: JHM
authors.lastname: Schellens
authors.affiliation: 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.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.affiliation: Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical Pharmacology, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Sparidans
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D002853:Chromatography, Liquid / Q000379:methods; D006801:Humans; D051379:Mice; D009281:Naphthalenes / Q000097:blood* / Q000493:pharmacokinetics*; D010865:Pilot Projects; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000097:blood* / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000097:blood* / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C507866:trans-1,2-dihydro-1,2-naphthalenediol; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D000225:Adenine
keywords: BTK inhibitor; Dihydrodiol-ibrutinib; Human plasma; Ibrutinib; LC–MS/MS; Mouse plasma