title: A novel HPLC-MS/MS method for the simultaneous determination of astemizole and its major metabolite in dog or monkey plasma and application to pharmacokinetics.
abstract: Astemizole (AST), a second-generation antihistamine, is metabolized to desmethyl astemizole (DEA), and although it has been removed from the market for inducing QT interval prolongation, it has reemerged as a potential anticancer and antimalarial agent. This report describes a novel high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for simultaneously determining the concentrations of AST and DEA in beagle dog and cynomolgus monkey plasma with simple preparation method and short retention time. Prior to HPLC analyses, the plasma samples were extracted with simple liquid-liquid extraction method. The isocratic mobile phase was 0.025% trifluoroacetic acid (TFA dissolved in acetonitrile) and 20 mM ammonium acetate (94:6) at a flow rate of 0.25 mL/min and diphenhydramine used as internal standard. In MS/MS analyses, precursor ions of the analytes were optimized as protonated molecular ions: [M+H](+). The lower limit of quantification of astemizole was 2.5 ng/mL in both species and desmethyl astemizole were 7.5 ng/mL and 10 ng/mL in dog and monkey plasma, respectively. The accuracy, precision, and stability of the method were in accordance with FDA guidelines for the validation of bioanalytical methods. Finally this validated method was successfully applied to a pharmacokinetic study in dogs and monkeys after oral administration of 10 mg/kg AST.
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea.
authors.forename: Hyun-moon
authors.initials: HM
authors.lastname: Back
authors.affiliation: General and Applied Toxicology Center, Korea Institute of Toxicology, Daejeon 305-600, Republic of Korea.
authors.forename: Jong-Hwa
authors.initials: JH
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea.
authors.forename: Jung-woo
authors.initials: JW
authors.lastname: Chae
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea.
authors.forename: Byungjeong
authors.initials: B
authors.lastname: Song
authors.affiliation: Research Center for Safety Pharmacology, Korea Institute of Toxicology, Daejeon 305-600, Republic of Korea.
authors.forename: Joung-Wook
authors.initials: JW
authors.lastname: Seo
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea.
authors.forename: Hwi-yeol
authors.initials: HY
authors.lastname: Yun
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea. Electronic address: kwon@cnu.ac.kr.
authors.forename: Kwang-il
authors.initials: KI
authors.lastname: Kwon
mesh_terms: D000284:Administration, Oral; D000818:Animals; D016589:Astemizole / Q000032:analysis* / Q000097:blood* / Q000493:pharmacokinetics; D002138:Calibration; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D004155:Diphenhydramine / Q000032:analysis; D004285:Dogs; D000882:Haplorhini; D059625:Liquid-Liquid Extraction; D008252:Macaca fascicularis; D015203:Reproducibility of Results; D013045:Species Specificity; D053719:Tandem Mass Spectrometry / Q000379:methods*; D014269:Trifluoroacetic Acid / Q000032:analysis
chemical_list: D016589:Astemizole; D004155:Diphenhydramine; D014269:Trifluoroacetic Acid
keywords: Astemizole; Desmethyl astemizole; LC–MS/MS; Pharmacokinetics