title: Pharmacokinetics and metabolite identification of a novel VEGFR-2 and Src dual inhibitor 6-chloro-2-methoxy-N-(2-methoxybenzyl) acridin-9-amine in rats by liquid chromatography tandem mass spectrometry.
abstract: A novel VEGFR-2 and Src dual inhibitor, 6-Chloro-2-methoxy-N-(2-methoxybenzyl) acridin-9-amine (MBAA), is a 9-aminoacridine derivative, but its pharmacokinetics and metabolism in body remain unknown. Using liquid chromatography tandem electrospray ionization mass spectrometry with the multiple reaction monitoring modes, we developed and validated a simple, rapid, sensitive and accurate technology for analyses of MBAA in the rat plasma, urine and bile. The micro samples were quickly prepared by 96-well plate. Chromatographic separation was performed on a C(18) column with gradient elution. High-quality linearity calibration curves were achieved over a concentration range of 1.00-3000 ng mL(-1). Intra- and inter-day precisions (RSD) were less than 8.5%, and accuracy (RE%) ranged from -2.9% to 12%. Extraction recoveries of MBAA were consistent with an average of 82.2-111.4% at three QC concentrations. When administered intravenously at a single dose of 2.0 mg kg(-1) to male SD rats, MBAA was rapidly eliminated with a T(1/2) of 0.9 ± 0.1h and AUC(0-t) of 369 ± 44.7 ng mL(-1). We identified four direct phase I and phase II metabolites by mass difference of molecular ions between metabolites and the parent compound. Various fragmentation patterns of MBAA were used to identify and characterize its metabolites. This LC-MS/MS analysis provides a useful approach to the pharmacokinetic and metabolic study of MBAA.
authors.affiliation: Department of Chemistry, Tsinghua University, Beijing 100084, PR China.
authors.forename: Yibao
authors.initials: Y
authors.lastname: Jin
authors.forename: Xudong
authors.initials: X
authors.lastname: Luan
authors.forename: Hongxia
authors.initials: H
authors.lastname: Liu
authors.forename: Chunmei
authors.initials: C
authors.lastname: Gao
authors.forename: Shangfu
authors.initials: S
authors.lastname: Li
authors.forename: Deliang
authors.initials: D
authors.lastname: Cao
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Li
authors.forename: Zongwei
authors.initials: Z
authors.lastname: Cai
authors.forename: Yuyang
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D000609:Aminoacridines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000818:Animals; D019540:Area Under Curve; D001646:Bile / Q000737:chemistry*; D001711:Biotransformation; D002138:Calibration; D002853:Chromatography, Liquid; D007275:Injections, Intravenous; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: C561100:6-chloro-2-methoxy-N-(2-methoxybenzyl)acridin-9-amine; D000609:Aminoacridines; D040301:Vascular Endothelial Growth Factor Receptor-2; D019061:src-Family Kinases