Metabolism of a new P-glycoprotein inhibitor HM-30181 in rats using liquid chromatography/electrospray mass spectrometry.
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-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-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-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.
Paek
In Bok
IB
Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy and Phytofermantation Research Center, Wonkwang University, Iksan 570-749, Korea.
Ji
Hye Young
HY
Kim
Maeng Sup
MS
Lee
Gwansun
G
Lee
Hye Suk
HS
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D001578:Benzopyrans / Q000032:analysis / Q000494:pharmacology*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003640:Dealkylation; D005243:Feces / Q000737:chemistry; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007275:Injections, Intravenous; D007546:Isoquinolines / Q000032:analysis / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization; D013777:Tetrazoles / Q000032:analysis / Q000494:pharmacology*
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; D007202:Indicators and Reagents; D007546:Isoquinolines; D013777:Tetrazoles