title: Enzyme kinetic study of a new cardioprotective agent, KR-32570 using human liver microsomes and recombinant CYP isoforms.
abstract: KR-32570 (5-(2-Methoxy-5-chlorophenyl)furan-2-ylcarbonyl)guanidine) is a new cardioprotective agent for preventing ischemia-reperfusion injury. Human liver microsomal incubation of KR-32570 in the presence of NADPH resulted in the formation of two metabolites, hydroxy-KR-32570 and O-desmethyl-KR-32570. In this study, a kinetic analysis of the metabolism of two metabolites from KR-32570 was performed in human liver microsomes, and recombinant CYP1A2, and CYP3A4. The metabolism for hydroxy- and O-desmethyl-KR-32570 formation from KR-32570 by human liver microsomes was best described by a Michaelis-Menten equation and a Hill equation, respectively. The Cl(int) values of hydroxy- and O-desmethyl-KR-32570 formation were similar to each other (0.03 vs 0.04 microL/min/pmol CYP, respectively). CYP3A4 mediated the formation of hydroxy-KR-32570 from KR-32570 with Cl(int) = 0.24 microL/min/pmol CYP3A4. The intrinsic clearance for O-desmethyl-KR-32570 formation by CYP1A2 was 0.83 AL/min/pmol CYP1A2. These findings suggest that CYP3A4 and CYP1A2 enzymes are major enzymes contributing to the metabolism of KR-32570.
authors.affiliation: Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Korea.
authors.forename: Hyojin
authors.initials: H
authors.lastname: Kim
authors.forename: Kyung-Ah
authors.initials: KA
authors.lastname: Seo
authors.forename: Hyunmi
authors.initials: H
authors.lastname: Kim
authors.forename: Hye Suk
authors.initials: HS
authors.lastname: Lee
authors.forename: Choong-Hwan
authors.initials: CH
authors.lastname: Lee
authors.forename: Jae-Gook
authors.initials: JG
authors.lastname: Shin
authors.forename: Kwang-Hyeon
authors.initials: KH
authors.lastname: Liu
mesh_terms: D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006146:Guanidines / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008862:Microsomes, Liver / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*
chemical_list: D027682:Cation Transport Proteins; D006146:Guanidines; D011994:Recombinant Proteins; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; C502305:(5-(2-methoxy-5-chloro-5-phenyl)furan-2-ylcarbonyl)guanidine; D003577:Cytochrome P-450 Enzyme System; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human