title: Determination of henatinib in human plasma and urine by liquid chromatography-tandem mass spectrometry and its pharmacokinetic application.
abstract: Henatinib is a novel oral small-molecule multikinase inhibitor that has demonstrated broad and potent antitumor activities in preclinical studies. In support of a clinical pharmacokinetic study, a simple, sensitive and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of henatinib in human plasma and urine. The sample preparation procedure involved a simple protein precipitation with methanol and the addition of midazolam as the internal standard. The chromatographic separation was achieved on an XBridge C18 column (50mm×2.1mm, 2.5μm) using a mixture of 5mM ammonium formate (pH 9.5)-acetonitrile-methanol (60:30:10, v/v/v) as the mobile phase. The MS/MS detection was performed in the positive ion multiple reaction monitoring (MRM) mode by monitoring the precursor→product ion transitions at m/z 469.1→382.2 for henatinib and m/z 326.2→291.3 for the internal standard. Assays were validated over the concentration range of 0.100-400ng/mL and 1.00-2500ng/mL for plasma and urine, respectively. The established method was highly sensitive with the lower limit of quantification (LLOQ) of 0.100ng/mL and 1.00ng/mL for plasma and urine, respectively. The intra- and inter-day precisions were <8.6% and <9.2% for plasma and urine, respectively. The mean assay accuracy was within ±6.8% of nominal values for both plasma and urine. The analytical runtime within 3.5min per sample made this method suitable for high-throughput determination. The validated method was successfully applied to a phase I dose escalation pharmacokinetic study in Chinese cancer patients.
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai 200032, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Qian
authors.forename: Yixuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Junning
authors.initials: J
authors.lastname: Cao
authors.forename: Jin
authors.initials: J
authors.lastname: Li
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001381:Azepines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002681:China; D002853:Chromatography, Liquid / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D057166:High-Throughput Screening Assays; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D057230:Limit of Detection; D009369:Neoplasms / Q000188:drug therapy; D012680:Sensitivity and Specificity; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; D007211:Indoles; C550539:2-((5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl)-5-(2-hydroxy-3-morpholinopropyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo(3,2-c)azepin-4-ketone