LC-MS/MS identification of in vitro metabolites of a new H+/K+ ATPase inhibitor, KR-60436 produced by rat and human liver microsomes.

摘要

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.