title: Dose-response relationships of FMISO between trace dose and various macro-doses in rat by ultra-performance liquid chromatography with mass spectrometry and radioactivity analysis.
abstract: Screening the pharmacokinetics of candidates using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) may be efficacious and safe for the research and development of new PET imaging agents. However, the PET imaging agent is administered as trace dose and the sensitivity of LC-MS/MS is often insufficient. If the dose was increased to be quantifiable, it should be necessary to prove whether the pharmacokinetics between trace and macro-doses is consistent or not. In this paper, fluoromisonidazole (FMISO), a tumor PET imaging agent, was chosen to evaluate the dose-response pharmacokinetics by administering various single intravenous doses (0.1, 0.4, 1.6 and 6.4 mg/kg) in male Sprague-Dawley rats. The plasma concentration of FMISO was determined by an ultra-performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method, and the blood radioactivity of [(18)F]FMISO was detected by a gamma counter. By calculating and comparing the pharmacokinetic parameters, the total area under the plasma concentration-time curve from time zero to infinity (AUC(0-∞)) and peak plasma concentration (C(max)) values increased with the selected FMISO doses, and showing linear dose-dependent. On the other hand, some parameters related to time, such as the elimination half-lives (t(1/2)) and elimination rate constant (K(e)) were dose-independent, and there is no significant deference between trace dose and various macro-doses. The data should be useful to evaluate the novel 2-nitroimidazole derivatives as potential PET tumor imaging agents.
authors.affiliation: Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, PR China.
authors.forename: Jinglei
authors.initials: J
authors.lastname: Du
authors.forename: Lin
authors.initials: L
authors.lastname: Zhu
authors.forename: Xue
authors.initials: X
authors.lastname: Zhou
authors.forename: Wei
authors.initials: W
authors.lastname: Yin
authors.forename: Aifang
authors.initials: A
authors.lastname: Deng
authors.forename: Jinping
authors.initials: J
authors.lastname: Qiao
mesh_terms: D000818:Animals; D019540:Area Under Curve; D002138:Calibration; D002851:Chromatography, High Pressure Liquid / Q000592:standards; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D006207:Half-Life; D007275:Injections, Intravenous; D016014:Linear Models; D008297:Male; D008657:Metabolic Clearance Rate; D008920:Misonidazole / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012015:Reference Standards; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D053719:Tandem Mass Spectrometry / Q000592:standards
chemical_list: D019275:Radiopharmaceuticals; C031843:fluoromisonidazole; D008920:Misonidazole