Document Detail

Characterization of human liver cytochrome P450 enzymes involved in the metabolism of a new H+/K+-ATPase inhibitor KR-60436.
MedLine Citation:
PMID:  15585365     Owner:  NLM     Status:  MEDLINE    
KR-60436 ([1-(4-methoxy-2-methylphenyl)-4-[(2-hydroxyethyl)amino]-6-trifluoromethoxy-2,3-dihydropyrrolo [3,2-c]quinoline]) is a new reversible H+/K+-ATPase inhibitor. The isoforms of human liver cytochrome P450 (CYP) responsible for the hepatic transformation of KR-60436 is identified. Dihydropyrrole oxidation and O-demethylation are major pathways for the metabolism of KR-60436 in human liver microsomes, whereas N-dehydroxyethylation and hydroxylation are minor pathways. The specific CYP isozymes responsible for KR-60436 oxidation to four major metabolites, pyrrole-KR-60436, O-demethylpyrrole-KR-60436, N-dehydroxyethyl-KR-60436 and an active metabolite, O-demethyl-KR-60436 were identified using the combination of correlation analysis, immuno-inhibition, chemical inhibition in human liver microsomes and metabolism by expressed recombinant CYP enzymes. The inhibitory potency of KR-60436 on clinically major CYPs was investigated in human liver microsomes. The results show that CYP3A4 contributes to the oxidation of KR-60436 to pyrrole-KR-60436, O-demethylpyrrole-KR-60436 and N-dehydroxyethyl-KR-60436, and CYP2C9 and CYP2D6 play roles in demethylation of KR-60436 to form the active metabolite, O-demethyl-KR-60436. KR-60436 was found to inhibit potently the metabolism of CYP1A2 substrates.
Hye Young Ji; Hye Won Lee; Hui-Hyun Kim; Joong-Kwon Choi; Hye Suk Lee
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Toxicology letters     Volume:  155     ISSN:  0378-4274     ISO Abbreviation:  Toxicol. Lett.     Publication Date:  2005 Jan 
Date Detail:
Created Date:  2004-12-08     Completed Date:  2005-02-09     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  7709027     Medline TA:  Toxicol Lett     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  103-14     Citation Subset:  IM    
Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy & Phytofermentation Research Center, Wonkwang University, Shinyongdong, Iksan 570-749, South Korea.
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MeSH Terms
Antibodies, Blocking / pharmacology
Chromatography, Liquid
Cytochrome P-450 Enzyme System / antagonists & inhibitors,  genetics,  metabolism*
DNA, Complementary / biosynthesis,  genetics
Enzyme Inhibitors / pharmacokinetics*
H(+)-K(+)-Exchanging ATPase / antagonists & inhibitors*
Isoenzymes / antagonists & inhibitors,  genetics,  metabolism
Liver / enzymology*
Mass Spectrometry
Microsomes, Liver / drug effects,  enzymology
Pyrroles / pharmacokinetics*
Quinolines / pharmacokinetics*
Reg. No./Substance:
0/1-(2-methyl-4-methoxyphenyl)-4-((2-hydroxyethyl)amino)-6-trifluoromethoxy-2,3-dihydropyrrolo(3,2-c)quinoline; 0/Antibodies, Blocking; 0/DNA, Complementary; 0/Enzyme Inhibitors; 0/Isoenzymes; 0/Pyrroles; 0/Quinolines; 9035-51-2/Cytochrome P-450 Enzyme System; EC ATPase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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