title: A rapid and efficient analytical method for the quantification of a novel anticholinergic compound, R-phencynonate, by stable isotope-dilution LC-MS/MS and its application to bioavailability and dose proportionality studies.
abstract: A rapid, specific and high-throughput stable isotope-dilution LC-MS/MS method was developed and validated with high sensitivity for the quantification of R-phencynonate (a eutomer of phencynonate racemate) in rat and dog plasma. Plasma samples were deproteinized using acetonitrile and then separated on a C8column with an isocratic mobile phase containing acetonitrile-water-formic acid mixture (60:40:0.1, v/v/v) at a flow rate of 0.2 mL/min. Each sample had a total run time of 3 min. Quantification was performed using triple quadrupole mass spectrometry in selected reaction monitoring mode with positive electrospray ionization. The method was shown to be highly linear (r2> 0.99) and to have a wide dynamic range (0.1-100 ng/mL) with favourable accuracy and precision. No matrix effects were observed. The detailed pharmacokinetic profiles of R-phencynonate at therapeutic doses in rats and dogs were characterized by rapid oral absorption, quick clearance, high volume of distribution and poor absolute bioavailability. R-Phencynonate lacked dose proportionality over the oral dose range, based on the power model. However, the area under concentration-time curve and the maximum plasma concentration increased linearly in a dose-dependent manner in both animal models. The absolute bioavailability of R-phencynonate was 16.6 ± 2.75 and 4.78 ± 1.26% in dogs and rats, respectively.
authors: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, People's Republic of China.
authors: Jinglai
authors: J
authors: Li
authors: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, People's Republic of China.
authors: Sha
authors: S
authors: Liao
authors: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, People's Republic of China.
authors: Xiaoying
authors: X
authors: Wang
authors: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, People's Republic of China.
authors: Qian
authors: Q
authors: Liu
authors: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, People's Republic of China.
authors: Fei
authors: F
authors: Meng
authors: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, People's Republic of China.
authors: Wenpeng
authors: W
authors: Zhang
authors: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, People's Republic of China.
authors: Tianhong
authors: T
authors: Zhang
authors: New Drug Safety Evaluation Center, Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing, People's Republic of China.
authors: Cuiping
authors: C
authors: Yang
authors: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, People's Republic of China.|Department of Preventive Medicine, Qinghai University School of Medicine, Xining, People's Republic of China.
authors: Xinyi
authors: X
authors: Song
authors: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, People's Republic of China.
authors: Huan
authors: H
authors: Luo
authors: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, People's Republic of China.
authors: Juan
authors: J
authors: Wang
authors: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, People's Republic of China.
authors: Zheng
authors: Z
authors: Li
authors: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, People's Republic of China.
authors: Bohua
authors: B
authors: Zhong
authors: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, People's Republic of China.
authors: Zhenqing
authors: Z
authors: Zhang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001372:Aza Compounds / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics*; D001682:Biological Availability; D018680:Cholinergic Antagonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D002853:Chromatography, Liquid / Q000379:methods*; D004285:Dogs; D006016:Glycolates / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics*; D008297:Male; D011865:Radioisotope Dilution Technique; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: C504860:3-methyl-3-azabicyclo(3,3,1)nonanyl-9-alpha-yl-alpha-cyclopentyl-alpha-phenyl-alpha-glycolate; D001372:Aza Compounds; D018680:Cholinergic Antagonists; D006016:Glycolates
keywords: R-phencynonate; bioavailability; dose proportionality; pharmacokinetics; stable isotope-dilution LC-MS/MS