title: Comparative study on pharmacokinetics of a series of anticholinergics, atropine, anisodamine, anisodine, scopolamine and tiotropium in rats.
abstract: The compound series of traditional anticholinergics [atropine (Atr), anisodamine (Ani), anisodine (AT3), and scopolamine (Sco)], naturally occurring belladonna alkaloid, have been approved for numerous therapeutic uses since 1970s. Tiotropium, a novel M receptor antagonist for the treatment of chronic obstructive pulmonary disease, was structurally modified based on atropine-like drugs. Clinical phenomena suggested that the changes of substituent group were related to the pharmacokinetic and pharmacodynamic characteristics of the agents. In an attempt to compare the pharmacokinetics of the series of anticholinergics and investigate the subsets motivating selective anticholinergic potencies, a sensitive LC-MS/MS method was established to analyze the differences of pharmacokinetic parameters. In this paper, we determined the pharmacokinetics of atropine, anisodamine, anisodine, scopolamine, and tiotropium after i.v. and i.g. single dose administration. After i.v. administration, the maximum drug plasma concentrations (C max) of Atr, Ani, AT3, and Sco were 274.25 ± 53.66, 267.50 ± 33.16, 340.50 ± 44.52, and 483.75 ± 78.13 ng/mL. Tiotropium had a slightly higher area under the curve with a significant increase of C max value. Because of their partial solubility, Atr, Ani, AT3, and Sco had different bioavailability in rats of 21.62, 10.78, 80.45 and 2.52 %, respectively. Following i.g. administration of tiotropium, the C max value below 20 ng/mL revealed the very low oral absorption. The urinary excretion rates of Atr, Ani, AT3, Sco and tiotropium were 11.33, 54.86, 32.67, 8.69 and 73.91 %. This work provided relatively comprehensive preclinical data on the series of anticholinergics, which may be used to explain the clinical adverse effects and applications.
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, Jiangsu, China.
authors.forename: Fengjie
authors.initials: F
authors.lastname: Tian
authors.forename: Cuiyun
authors.initials: C
authors.lastname: Li
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Shuangxia
authors.initials: S
authors.lastname: Ren
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.forename: Sufeng
authors.initials: S
authors.lastname: Zhou
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
authors.forename: Di
authors.initials: D
authors.lastname: Zhao
authors.forename: Xijing
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D001285:Atropine / Q000493:pharmacokinetics*; D018680:Cholinergic Antagonists / Q000493:pharmacokinetics*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012601:Scopolamine / Q000493:pharmacokinetics*; D012602:Scopolamine Derivatives / Q000493:pharmacokinetics*; D012991:Solanaceous Alkaloids / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry; D000069447:Tiotropium Bromide / Q000493:pharmacokinetics*
chemical_list: D018680:Cholinergic Antagonists; D012602:Scopolamine Derivatives; D012991:Solanaceous Alkaloids; C003922:anisodamine; D001285:Atropine; D012601:Scopolamine; D000069447:Tiotropium Bromide; C012183:anisodine
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