title: Design, synthesis, and cholesterol-lowering efficacy for prodrugs of berberrubine.
abstract: In order to enhance oral bioavailability of berberine (BBR) for its cholesterol-lowering efficacy in vivo, a series of ester or ether prodrugs of berberrubine (M1), which is an active metabolite of BBR after first-pass metabolism, were designed, semi-synthesized, and evaluated. Among these M1 prodrugs, compound 5g possessing palmitate at the 9-position showed a moderate LogP value and esterase hydrolysis rate for releasing M1 in blood. Its cholesterol-lowering efficacy in vivo was evaluated in hyperlipidemic SD rats. Compound 5g (100mg/kg/d) reduced blood CHO and LDL-c by 35.8% and 45.5%, respectively, similar to that by BBR. It also exhibited a good safety in rats with no side-effect on liver and kidney function. Therefore, the design of M1 prodrug appears to be an effective strategy to improve pharmacokinetic feature of BBR for its lipid-lowering efficacy in vivo.
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Ying-Hong
authors.initials: YH
authors.lastname: Li
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Peng
authors.initials: P
authors.lastname: Yang
authors.forename: Wei-Jia
authors.initials: WJ
authors.lastname: Kong
authors.forename: Xue-Fu
authors.initials: XF
authors.lastname: You
authors.forename: Gang
authors.initials: G
authors.lastname: Ren
authors.forename: Hong-Bin
authors.initials: HB
authors.lastname: Deng
authors.forename: Yue-Ming
authors.initials: YM
authors.lastname: Wang
authors.forename: Yan-Xiang
authors.initials: YX
authors.lastname: Wang
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Jiang
authors.forename: Dan-Qing
authors.initials: DQ
authors.lastname: Song
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001599:Berberine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D002784:Cholesterol / Q000097:blood; D006949:Hyperlipidemias / Q000097:blood / Q000188:drug therapy; D008297:Male; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000924:Anticholesteremic Agents; D011355:Prodrugs; D001599:Berberine; C115958:berberrubine; D002784:Cholesterol