title: In vitro metabolism of a new cardioprotective agent, KR-33028 in the human liver microsomes and cryopreserved human hepatocytes.
abstract: KR-33028 (N-[4-cyano-benzo[b]thiophene-2-carbonyl]guanidine) is a new cardioprotective agent for preventing ischemia-reperfusion injury. This study was performed to identify the metabolic pathway of KR-33028 in human liver microsomes and to compare its metabolism with that of cryopreserved human hepatocytes. Human liver microsomal incubation of KR-33028 in the presence of NADPH and UDPGA resulted in the formation of four metabolites, M1, M2, M3, and M4. M1 and M2 were identified as 5-hydroxy-KR-33028 and 7-hydroxy-KR-33028, respectively, on the basis of LC/MS/MS analysis with the synthesized authentic standard. M3 and M4 were suggested to be dihydroxy-KR-33028 and hydroxy-KR-33028-glucuronide, respectively. Metabolism of KR-33028 in cryopreserved human hepatocytes resulted in the formation of M1, M2, and M4. These data show a good correlation between major metabolites formed in human liver microsomes and cryopreserved human hepatocytes. In addition, KR-33028 was found to inhibit moderately the metabolism of CYP1A2 substrates. Based on the results obtained metabolic pathway of KR-33028 is proposed.
authors.affiliation: Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 614-735, Korea.
authors.forename: Hyojin
authors.initials: H
authors.lastname: Kim
authors.forename: Yune-Jung
authors.initials: YJ
authors.lastname: Yoon
authors.forename: Hyunmi
authors.initials: H
authors.lastname: Kim
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Cha
authors.forename: Hye Suk
authors.initials: HS
authors.lastname: Lee
authors.forename: Jeong-Han
authors.initials: JH
authors.lastname: Kim
authors.forename: Kyu Yang
authors.initials: KY
authors.lastname: Yi
authors.forename: Sunkyung
authors.initials: S
authors.lastname: Lee
authors.forename: Hyae Gyeong
authors.initials: HG
authors.lastname: Cheon
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Yoo
authors.forename: Sang-Seop
authors.initials: SS
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: D001711:Biotransformation; D002316:Cardiotonic Agents / Q000378:metabolism*; D015925:Cryopreservation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D020719:Glucuronides / Q000378:metabolism; D006146:Guanidines / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007527:Isoenzymes / Q000378:metabolism; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D009249:NADP / Q000096:biosynthesis; D013876:Thiophenes / Q000378:metabolism*
chemical_list: D002316:Cardiotonic Agents; D020719:Glucuronides; D006146:Guanidines; D007202:Indicators and Reagents; D007527:Isoenzymes; C507425:N-(4-cyano-benzo(b)thiophene-2-carbonyl)guanidine; D013876:Thiophenes; D009249:NADP; D003577:Cytochrome P-450 Enzyme System