Characterization of human liver cytochrome P450 enzymes involved in the metabolism of a new H+/K+-ATPase inhibitor KR-60436.
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.
Ji
Hye Young
HY
Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy & Phytofermentation Research Center, Wonkwang University, Shinyongdong, Iksan 570-749, South Korea.
Lee
Hye Won
HW
Kim
Hui-Hyun
HH
Choi
Joong-Kwon
JK
Lee
Hye Suk
HS
D019138:Antibodies, Blocking / Q000494:pharmacology; D001711:Biotransformation; D002853:Chromatography, Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010084:Oxidation-Reduction; D054328:Proton Pump Inhibitors; D011758:Pyrroles / Q000493:pharmacokinetics*; D011804:Quinolines / Q000493:pharmacokinetics*; D014162:Transfection
C439392:1-(2-methyl-4-methoxyphenyl)-4-((2-hydroxyethyl)amino)-6-trifluoromethoxy-2,3-dihydropyrrolo(3,2-c)quinoline; D019138:Antibodies, Blocking; D065607:Cytochrome P-450 Enzyme Inhibitors; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D054328:Proton Pump Inhibitors; D011758:Pyrroles; D011804:Quinolines; D003577:Cytochrome P-450 Enzyme System