title: Characterization of human liver cytochrome P-450 enzymes involved in the O-demethylation of a new P-glycoprotein inhibitor HM-30181.
abstract: HM-30181, 4-oxo-4H-chromene-2-carboxylic acid [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-amide, is a new P-glycoprotein inhibitor with the potential to increase the cytotoxic activity of orally coadministered paclitaxel. This study was performed to characterize human cytochrome P-450 (CYP) enzymes involved in the metabolism of HM-30181 to 4- or 5-O-desmethyl-HM-30181 (M2) and 6- or 7-O-desmethyl-HM-30181 (M3) and to investigate the inhibitory potential of HM-30181 on CYP enzymes in human liver microsomes. CYP3A4 was identified as the major isozyme responsible for the O-demethylation of HM-30181 to M2 and M3 based on the correlation analysis, chemical inhibition and immuno-inhibition study and metabolism in cDNA-expressed human CYP isozymes. HM-30181 itself had no inhibitory effects on CYPs 1A2, 2A6, 2C8, 2C9, 2C19, 2D6, and 3A4 in human liver microsomes, suggesting the possibility that the pharmacokinetics of HM-30181 could be changed with coadministration of known CYP3A4 inducers or inhibitors.
authors.affiliation: Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, Wonkwang University, Iksan, Republic of Korea.
authors.forename: In Bok
authors.initials: IB
authors.lastname: Paek
authors.forename: Sung Yeon
authors.initials: SY
authors.lastname: Kim
authors.forename: Maeng Sup
authors.initials: MS
authors.lastname: Kim
authors.forename: John
authors.initials: J
authors.lastname: Kim
authors.forename: Gwansun
authors.initials: G
authors.lastname: Lee
authors.forename: Hye Suk
authors.initials: HS
authors.lastname: Lee
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D001578:Benzopyrans / Q000378:metabolism* / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D018076:DNA, Complementary / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000378:metabolism* / Q000493:pharmacokinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010090:Oxidoreductases, O-Demethylating; D013777:Tetrazoles / Q000378:metabolism* / Q000493:pharmacokinetics
chemical_list: C521083:4-oxo-4H-chromene-2-carboxylic acid (2-(2-(4-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl)-phenyl)-2H-tetrazol-5-yl)-4,5-dimethoxyphenyl)amide; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001578:Benzopyrans; D018076:DNA, Complementary; D007546:Isoquinolines; D013777:Tetrazoles; D003577:Cytochrome P-450 Enzyme System; D010090:Oxidoreductases, O-Demethylating; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human