Characterization of human liver cytochrome P-450 enzymes involved in the O-demethylation of a new P-glycoprotein inhibitor HM-30181.
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.
Paek
In Bok
IB
Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, Wonkwang University, Iksan, Republic of Korea.
Kim
Sung Yeon
SY
Kim
Maeng Sup
MS
Kim
John
J
Lee
Gwansun
G
Lee
Hye Suk
HS
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
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