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Metabolism of a new P‐glycoprotein inhibitor HM‐30181 in rats using liquid chromatography/electrospray mass spectrometry
Author(s) -
Paek In Bok,
Ji Hye Young,
Kim Maeng Sup,
Lee Gwansun,
Lee Hye Suk
Publication year - 2006
Publication title -
rapid communications in mass spectrometry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.528
H-Index - 136
eISSN - 1097-0231
pISSN - 0951-4198
DOI - 10.1002/rcm.2468
Subject(s) - chemistry , chromatography , amide , hydroxylation , liquid chromatography–mass spectrometry , demethylation , in vivo , microsome , mass spectrometry , urine , metabolism , tandem mass spectrometry , hydrolysis , metabolite , electrospray mass spectrometry , electrospray , in vitro , enzyme , biochemistry , gene expression , microbiology and biotechnology , biology , dna methylation , gene
HM‐30181, 4‐oxo‐4 H ‐chromene‐2‐carboxylic acid, [2‐(2‐{4‐[2‐(6,7‐dimethoxy‐3,4‐dihydro‐1 H ‐isoquinolin‐2‐yl)‐ethyl]‐phenyl}‐2 H ‐tetrazol‐5‐yl)‐4,5‐dimethoxyphenyl]amide, is a new P‐glycoprotein inhibitor. This study was performed to identify the in vitro and in vivo metabolic pathway of HM‐30181 in rats. Rat liver microsomal incubation of HM‐30181 in the presence of NADPH resulted in the formation of four metabolites, M1–M4. M1 and M2 were identified as 2‐(2‐{4‐[2‐(6,7‐dimethoxy‐3,4‐dihydro‐1 H ‐isoquinolin‐2‐yl)‐ethyl]‐phenyl}‐2 H ‐tetrazol‐5‐yl)‐4,5‐dimethoxyaniline and 4‐ or 5‐ O ‐desmethyl‐HM‐30181, respectively, on the basis of liquid chromatography/tandem mass spectrometry (LC/MS/MS) analysis with the synthesized authentic standards. M3 and M4 were suggested to be 6‐ or 7‐ O ‐desmethyl‐HM‐30181 and hydroxy‐HM‐30181, respectively. These in vitro metabolites were also detected in feces and urine samples after an intravenous administration of HM‐30181 to male rats. The metabolic routes for HM‐30181 were O‐demethylation of the methoxy group to M2 and M3, hydrolysis of the amide group to M1, and hydroxylation to M4. Copyright © 2006 John Wiley & Sons, Ltd.