title: A rapid and sensitive LC-MS/MS method for evaluation of the absolute oral bioavailability of a novel c-Met tyrosine kinase inhibitor QBH-196 in rats.
abstract: A sensitive, selective and high-throughput UPLC-MS/MS method was developed and validated for the determination of a novel c-Met tyrosine kinase inhibitor, QBH-196, in rat plasma. QBH-196 and its analog BH357 (IS) were extracted from rat plasma using a mixture of dichloromethane and N-hexane (2:3, v/v). The chromatographic separation was carried out on Phenomenex C18 column (50 × 2.1 mm, 2.6 µm particle size) with a gradient mobile phase of methanol (A) and water containing 0.05% formic acid (B) at a flow rate of 0.2 mL/min. The assay was performed by positive electrospray ionization in multiple reaction monitoring mode using transitions of m/z 622.68 → 140.41 for QBH-196 and m/z 591.19 →126.21 for the IS, respectively. Good linearity was obtained over the concentration range of 8.0-4000 ng/mL (r(2) > 0.99) for QBH-196 and the lower limit of quantification was 8.0 ng/mL in rat plasma. Validations of the method, including its sensitivity, extraction recovery, matrix effect, intra- and inter-day precision, accuracy and stability, were all within acceptable limits. The established method was successfully applied to determine absolute oral bioavailability of QBH-196 in rats for the first time. The mean oral absolute bioavailability of QBH-196 was found to be about 40.8% and the elimination half-life was 40.0 ± 13.1 h. This result suggested that QBH-196 exhibits good oral absorption in vivo, which is very important for the further development of QBH-196 as a new oral anticancer drug.
authors.affiliation: Department of Biopharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Biopharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Biopharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Tianshu
authors.initials: T
authors.lastname: Lu
authors.affiliation: Department of Biopharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Jinling
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Biopharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Chunnuan
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Biopharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Biopharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Zhonggui
authors.initials: Z
authors.lastname: He
authors.affiliation: Key Laboratory of Structure-Based Drugs Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Biopharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Liu
mesh_terms: D000818:Animals; D001682:Biological Availability; D002853:Chromatography, Liquid / Q000379:methods*; D057230:Limit of Detection; D008297:Male; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D011804:Quinolines / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015203:Reproducibility of Results; D012663:Semicarbazides / Q000097:blood / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: C587053:N1-(3-fluoro-4-(6-methoxy-7-(3-(4-methylpiperidin-1-yl)propoxy)quinolin-4-yloxy)phenyl)-N4-(2,4-difluorobenzylidene)semicarbazide; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D012663:Semicarbazides; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases
keywords: LC-MS/MS; QBH-196; bioavailability; c-Met tyrosine kinase inhibitors