title: Identification of circulatory and excretory metabolites of a novel nitric oxide donor ZJM-289 in rat plasma, bile, urine and faeces by liquid chromatography-tandem mass spectrometry.
abstract: ZJM-289, [2-(1-diethylaminoacetoxy)pentyl] benzoic acid-{2-methoxy-4-[2-(4-nitrooxybutoxy carbonyl)-vinyl]}phenyl ester hydrochloride, is a novel nitric oxide-donating derivative of 3-n-butylphthalide synthesised on the hypothesis that it may be hydrolysed in vivo into 3-n-butylphthalide, ferulic acid and nitric oxide in hope that the three components may exert effects on the platelets as well as on central nervous system synergistically. In this study, ZJM-289 was extensively metabolised in rats. Eight major metabolites were identified by liquid chromatography (LC)-mass spectrometry (MS)/MS in rat plasma, bile, urine and faeces after intravenous administration. Metabolites M1, M2, M3, M4 and M5 were hydrolytic products of ZJM-289, M6 and M7 was a hydroxylation product of M5, and M8 was a glucuronide of M1. The pharmacologically active metabolite ferulic acid (M3) was a major metabolite in all the biological matrixes examined. 3-n-Butylphthalide was also present at a moderate level in the circulation. And along with the previous research, the anti-platelet activity of ZJM-289 was more potent than that of 3-n-butylphthalide both in vivo and in vitro. All these findings validated the theory of drug design.
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Xuliang
authors.initials: X
authors.lastname: Wang
authors.forename: Tingting
authors.initials: T
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Ji
authors.forename: Yihua
authors.initials: Y
authors.lastname: Zhang
authors.forename: Zhixia
authors.initials: Z
authors.lastname: Qiu
authors.forename: Di
authors.initials: D
authors.lastname: Zhao
authors.forename: Xijing
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D001646:Bile / Q000737:chemistry*; D002853:Chromatography, Liquid; D002934:Cinnamates / Q000032:analysis / Q000097:blood / Q000737:chemistry / Q000652:urine; D005243:Feces / Q000737:chemistry*; D007275:Injections, Intravenous; D008297:Male; D053858:Metabolic Networks and Pathways; D009566:Nitrates / Q000032:analysis / Q000097:blood / Q000737:chemistry / Q000652:urine; D020030:Nitric Oxide Donors / Q000032:analysis* / Q000097:blood / Q000737:chemistry / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry / Q000379:methods*; D013997:Time Factors
chemical_list: C554089:(2-(1-diethylaminoacetoxy)pentyl)benzoic acid (2-methoxy-4-(2-(4-nitrooxybutoxycarbonyl)vinyl))phenyl ester; D002934:Cinnamates; D009566:Nitrates; D020030:Nitric Oxide Donors