title: Quantitative determination of regorafenib and its two major metabolites in human plasma with high-performance liquid chromatography and ultraviolet detection.
abstract: A simple, highly sensitive and specific high-performance liquid chromatography (HPLC) method was developed for the simultaneous quantitation of regorafenib, N-oxidemetabolite (M-2) and the desmethyl N-oxide metabolite (M-5) in human plasma. Regorafenib, M-2, M-5 and the internal standard sorafenib were separated using a mobile phase of 0.5% KH2 PO4 (pH 3.5)-acetonitrile (30:70, v/v), on a Capcell PAK MG II column at a flow rate of 0.5 mL/min and measurement at UV 260 nm. The lower limits of quantification for regorafenib, M-2 and M-5 were 10 ng/mL for each analyte. A procedure using solid-phase extraction required only a small amount of plasma (100 μL) for one analysis while providing high extraction recovery (>81% for all compounds) and good selectivity. Coefficients of variation for intra- and inter-day assays were <12.2% for regorafenib, <12.3% for M-2 and <15.1% for M-5. Accuracies for intra- and inter-day assays were <9.4% for regorafenib, <8.0% for M-2 and <12.8% for M-5 over a linear range from 10 to 10,000 ng/mL. This HPLC assay is suitable for clinical pharmacokinetic studies of regorafenib. The present HPLC method is currently in use for our observational studies of patients under treatment. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Department of Pharmacy, Akita University Hospital, Akita, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Fujita
authors.affiliation: Department of Pharmacy, Akita University Hospital, Akita, Japan.
authors.forename: Masatomo
authors.initials: M
authors.lastname: Miura
authors.affiliation: Department of Clinical Oncology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shibata
mesh_terms: D002138:Calibration; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D006801:Humans; D057230:Limit of Detection; D010671:Phenylurea Compounds / Q000097:blood* / Q000493:pharmacokinetics; D011725:Pyridines / Q000097:blood* / Q000493:pharmacokinetics; D012015:Reference Standards; D015203:Reproducibility of Results; D013056:Spectrophotometry, Ultraviolet / Q000379:methods*
chemical_list: D010671:Phenylurea Compounds; D011725:Pyridines; C559147:regorafenib
keywords: HPLC; human plasma; metabolite; regorafenib