title: Study of in vitro metabolism of m-nisoldipine in human liver microsomes and recombinant cytochrome P450 enzymes by liquid chromatography-mass spectrometry.
abstract: This is a report about the investigation of the metabolic fate of m-nisoldipine in human liver microsomes and the recombinant cytochrome P450 enzymes by using LC-MS/MS. A sensitive and reliable LC-MS/MS method was developed to obtain a rapid and complete characterization of new metabolites and the metabolism pathways. The analytes were separated on a reversed phase C18 column with acetonitrile and 0.1% aqueous formic acid as the mobile phase. Tandem mass spectrometry with positive electrospray ionization was used to enable the structural characterization of the metabolites. A total of 10 metabolites were characterized with proposed structures in the incubation of human liver microsomes by comparing their retention times and spectral patterns with those of the parent drug. Dehydrogenation of the dihydropyridine core and reactions of side chains such as hydroxylation and hydrolysis of ester bonds were the major metabolic pathways. The specific cytochrome P450 (CYP) enzymes responsible for m-nisoldipine metabolites were identified using chemical inhibition and cDNA expressed CYP enzymes. The results indicated that CYP2C19 and CYP3A4 might play major roles in the metabolism of m-nisoldipine in human liver microsomes.
authors.affiliation: Department of Pharmaceutical Analysis, School of Pharmacy, Hebei Medical University, Shijiazhuang, PR China.
authors.forename: Lin
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Department of Pharmaceutical Analysis, School of Pharmacy, Hebei Medical University, Shijiazhuang, PR China.
authors.forename: Peipei
authors.initials: P
authors.lastname: Jia
authors.affiliation: Department of Pharmaceutical Analysis, School of Pharmacy, Hebei Medical University, Shijiazhuang, PR China.
authors.forename: Yupeng
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Pharmaceutical Analysis, School of Pharmacy, Hebei Medical University, Shijiazhuang, PR China.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Department of Pharmaceutical Analysis, School of Pharmacy, Hebei Medical University, Shijiazhuang, PR China.
authors.forename: Xuran
authors.initials: X
authors.lastname: Zhi
authors.affiliation: Department of Pharmaceutical Analysis, School of Pharmacy, Hebei Medical University, Shijiazhuang, PR China.
authors.forename: Ning
authors.initials: N
authors.lastname: Sheng
authors.affiliation: Department of Pharmaceutical Analysis, School of Pharmacy, Hebei Medical University, Shijiazhuang, PR China. Electronic address: zhanglantong@263.net.
authors.forename: Lantong
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000959:Antihypertensive Agents / Q000378:metabolism*; D002853:Chromatography, Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D015737:Nisoldipine / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry
chemical_list: D000959:Antihypertensive Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D011994:Recombinant Proteins; D015737:Nisoldipine; D003577:Cytochrome P-450 Enzyme System
keywords: Human liver microsomes; LC–MS/MS; Metabolism; Recombinant cytochrome P450 enzymes; m-Nisoldipine