title: LC-MS/MS identification of in vitro metabolites of a new H+/K+ ATPase inhibitor, KR-60436 produced by rat and human liver microsomes.
abstract: The metabolism of a new H+/K+ ATPase inhibitor, KR-60436 [1-(4-methoxy-2-methyl-phenyl)-4-[(2-hydroxyethyl)amino]-6-trifluoromethoxy-2,3-dihydropyrrolo[3,2-c]quinoline] has been studied by LC-electrospray mass spectrometry. In vitro incubation of KR-60436 with rat and human liver microsomes in the presence of NADPH produced seven metabolites (M1-M7). M3-M6 were identified as O-demethyl-KR-60436, O-demethyl-pyrrole-KR-60436, N-dehydroxyethyl-KR-60436 and pyrrole-KR-60436, respectively, based on LC/MS/MS analysis with authentic standards. M1, M2 and M7 were tentatively identified as monohydroxylated-KR-60436, monohydroxylated-pyrrole-KR-60436 and N-dehydroxyethyl-pyrrole-KR-60436, respectively. The four principal metabolic pathways are characterized in KR-60436 metabolism: oxidation of dihydropyrrole ring to pyrrole, O-demethylation of methoxy group, hydroxylation of quinoline moiety and N-dealkylation of hydroxyethylamino group.
authors.affiliation: Bioanalysis Laboratory, College of Pharmacy and Medicinal Resources Research Center, Wonkwang University, Shinyongdong, 570-749, Iksan, South Korea.
authors.forename: Sung Jin
authors.initials: SJ
authors.lastname: Choi
authors.forename: Hye Young
authors.initials: HY
authors.lastname: Ji
authors.forename: Soo Kyung
authors.initials: SK
authors.lastname: Baek
authors.forename: Hee-Yong
authors.initials: HY
authors.lastname: Lee
authors.forename: Joong-Kwon
authors.initials: JK
authors.lastname: Choi
authors.forename: Hyae Gyeong
authors.initials: HG
authors.lastname: Cheon
authors.forename: Dong Ha
authors.initials: DH
authors.lastname: Lee
authors.forename: Hong
authors.initials: H
authors.lastname: Lim
authors.forename: Hye Suk
authors.initials: HS
authors.lastname: Lee
mesh_terms: D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D054328:Proton Pump Inhibitors; D011758:Pyrroles / Q000032:analysis / Q000493:pharmacokinetics*; D011804:Quinolines / Q000032:analysis / Q000493:pharmacokinetics*; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: C439392:1-(2-methyl-4-methoxyphenyl)-4-((2-hydroxyethyl)amino)-6-trifluoromethoxy-2,3-dihydropyrrolo(3,2-c)quinoline; D004791:Enzyme Inhibitors; D054328:Proton Pump Inhibitors; D011758:Pyrroles; D011804:Quinolines