title: Synthesis of a highly water-soluble acacetin prodrug for treating experimental atrial fibrillation in beagle dogs.
abstract: We previously reported that duodenal administration of the natural flavone acacetin can effectively prevent the induction of experimental atrial fibrillation (AF) in canines; however, it may not be used intravenously to terminate AF due to its poor water-solubility. The present study was to design a water-soluble prodrug of acacetin and investigate its anti-AF effect in beagle dogs. Acacetin prodrug was synthesized by a three-step procedure. Aqueous solubility, bioconversion and anti-AF efficacy of acacetin prodrug were determined with different methodologies. Our results demonstrated that the synthesized phosphate sodium salt of acacetin prodrug had a remarkable increase of aqueous solubility in H2O and clinically acceptable solution (5% glucose or 0.9% NaCl). The acacetin prodrug was effectively converted into acacetin in ex vivo rat plasma and liver microsome, and in vivo beagle dogs. Intravenous infusion of acacetin prodrug (3, 6 and 12 mg/kg) terminated experimental AF without increasing ECG QTc interval in beagle dogs. The intravenous LD50 of acacetin prodrug was 721 mg/kg in mice. Our preclinical study indicates that the synthesized acacetin prodrug is highly water-soluble and safe; it effectively terminates experimental AF in beagle dogs and therefore may be a promising drug candidate for clinical trial to treat patients with acute AF.
authors.affiliation: Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China.|Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China.|Department of Pharmacy Engineering Specialty, College of Chemistry and Chemical Engineering, Guangxi University, Nanning, Guangxi, 530004 China.
authors.forename: Ya-Jing
authors.initials: YJ
authors.lastname: Wang
authors.affiliation: Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China.|Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China.
authors.forename: Man-Wen
authors.initials: MW
authors.lastname: Jin
authors.affiliation: Xiamen Cardiovascular Hospital, Medical College of Xiamen University, Xiamen, Fujian, 361004 China.
authors.forename: Guo-Sheng
authors.initials: GS
authors.lastname: Xiao
authors.affiliation: Xiamen Cardiovascular Hospital, Medical College of Xiamen University, Xiamen, Fujian, 361004 China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China.
authors.forename: Hai-Ying
authors.initials: HY
authors.lastname: Sun
authors.affiliation: Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China.|Xiamen Cardiovascular Hospital, Medical College of Xiamen University, Xiamen, Fujian, 361004 China.
authors.forename: Gui-Rong
authors.initials: GR
authors.lastname: Li
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000097:blood / Q000188:drug therapy*; D004285:Dogs; D047309:Flavones / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008813:Mice, Inbred ICR; D015221:Potassium Channels / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D012995:Solubility; D023382:Toxicity Tests, Acute; D014630:Vagus Nerve / Q000187:drug effects; D014867:Water / Q000737:chemistry*
chemical_list: D047309:Flavones; D015221:Potassium Channels; D011355:Prodrugs; D014867:Water; C023717:acacetin