title: Pharmacokinetics and tissue distribution of ginkgolide A, ginkgolide B, and ginkgolide K after intravenous infusion of ginkgo diterpene lactones in a rat model.
abstract: Ginkgo diterpene lactones are compounds that are extracted from the Ginkgo biloba leaf and possess pharmacologic activities with neuroprotective effects. To address the poor bioavailability of ginkgo diterpene lactones, ginkgo diterpene lactone meglumine injection (GDLI) was formulated and is commercially available. In this study, a simple, sensitive and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for assessing the total amount and the amount of the prototype forms of ginkgolides A (GA), B (GB) and K (GK) in rat plasma and tissues. This method was used to calculate the concentrations of the hydrolysed carboxylic forms and assess the pharmacokinetics of the ginkgolides after intravenous (i.v.) GDLI administration in rats. Generally, all three ginkgolide forms showed dose-dependent plasma concentrations, and no obvious differences in pharmacokinetic parameters, i.e., area under the curve (AUC) of plasma concentration versus time and half-life, were observed after GDLI administration on 7 consecutive days. These ginkgolides primarily existed in the carboxylic form in the plasma, and the systemic concentrations of the carboxylic forms of GA and GB were 11- to 17- and 3- to 4-fold higher than those of their prototype forms, respectively. In contrast, dramatically increased levels of the GA and GB prototype lactones were detected in the liver and heart. GA, GB, and GK were extensively distributed in various organs/tissues; the highest levels were found in the kidneys, liver, and intestine, and the lowest levels were found in the brain. These data suggest that ginkgolides have difficulty crossing the blood-brain barrier and that their targets for protecting against cerebral ischaemia are located outside the central system.
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China; Jiangsu Kanion Modern Chinese Medicine Institute, Nanjing 210017, China.
authors.forename: Shuyao
authors.initials: S
authors.lastname: Wang
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Bingchen
authors.initials: B
authors.lastname: Ouyang
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Jiye
authors.initials: J
authors.lastname: Aa
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Jianliang
authors.initials: J
authors.lastname: Geng
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Fei
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Wang
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Jiankun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Jiangsu Kanion Modern Chinese Medicine Institute, Nanjing 210017, China; State Key Laboratory of Pharmaceutical New-Tech for Chinese Medicine, Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang 222001, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Geng
authors.affiliation: Jiangsu Kanion Modern Chinese Medicine Institute, Nanjing 210017, China; State Key Laboratory of Pharmaceutical New-Tech for Chinese Medicine, Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang 222001, China.
authors.forename: Yanjing
authors.initials: Y
authors.lastname: Li
authors.affiliation: Jiangsu Kanion Modern Chinese Medicine Institute, Nanjing 210017, China; State Key Laboratory of Pharmaceutical New-Tech for Chinese Medicine, Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang 222001, China.
authors.forename: Wenzhe
authors.initials: W
authors.lastname: Huang
authors.affiliation: Jiangsu Kanion Modern Chinese Medicine Institute, Nanjing 210017, China; State Key Laboratory of Pharmaceutical New-Tech for Chinese Medicine, Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang 222001, China.
authors.forename: Zhenzhong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China; Jiangsu Kanion Modern Chinese Medicine Institute, Nanjing 210017, China; State Key Laboratory of Pharmaceutical New-Tech for Chinese Medicine, Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang 222001, China. Electronic address: xw_kanion@163.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: guangjiwang@hotmail.com.
authors.forename: Guangji
authors.initials: G
authors.lastname: Wang
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000378:metabolism; D002853:Chromatography, Liquid / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D005260:Female; D046934:Ginkgolides / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D006207:Half-Life; D007262:Infusions, Intravenous; D007783:Lactones / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry / Q000379:methods*; D014018:Tissue Distribution
chemical_list: D046934:Ginkgolides; D007783:Lactones; C481151:ginkgolide K; C045856:ginkgolide B; C477042:ginkgolide A
keywords: Ginkgo diterpene lactones; Hydrolysates of ginkgolides; LC–MS/MS; Pharmacokinetics; Tissue distribution