title: Determination of a novel anticancer c-Met inhibitor LS-177 in rat plasma and tissues with a validated UPLC-MS/MS method: application to pharmacokinetics and tissue distribution study.
abstract: LS-177 is a novel small-molecule kinase inhibitor employed to interrupt the c-Met signaling pathway. A rapid and sensitive ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for determination of LS-177 in rat plasma and tissues. The biosamples were extracted by liquid-liquid extraction with methyl tert-butyl ether and separated on a C18 column (50 × 4.6 mm, 2.6 µm) using a gradient elution mobile phase consisting of acetonitrile-0.1% formic acid water. Under the optimal conditions, the selectivity of the method was satisfactory with no endogenous interference. The intraday and interday precisions (relative standard deviation) were <10.5% and the accuracy (relative error) was from -12.5 to 12.5% at all quality control levels. Excellent recovery and negligible matrix effects were observed. Stability studies showed that LS-177 was stable during the preparation and analytical processes. The UPLC-MS/MS method was successfully applied to pharmacokinetic and tissue distribution studies. The results indicated that there was no significant drug accumulation after multiple-dose oral administration of LS-177. The tissue distribution study exhibited significant higher uptakes of LS-177 in stomach, intestine, lung and liver among all of the tissues. The results in pharmacokinetics and tissue distribution may provide a meaningful basis for clinical application.
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Ju
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China.
authors.forename: Simin
authors.initials: S
authors.lastname: Zhao
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China.
authors.forename: Lunhui
authors.initials: L
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China.
authors.forename: Liqiang
authors.initials: L
authors.lastname: Gu
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Tang
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China.
authors.forename: Kaishun
authors.initials: K
authors.lastname: Bi
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000032:analysis* / Q000737:chemistry / Q000493:pharmacokinetics; D004355:Drug Stability; D005260:Female; D016014:Linear Models; D008297:Male; D047428:Protein Kinase Inhibitors / Q000032:analysis* / Q000737:chemistry / Q000493:pharmacokinetics; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met
keywords: LS-177; UPLC-MS/MS; pharmacokinetics; tissue distribution