Enzyme kinetic study of a new cardioprotective agent, KR-32570 using human liver microsomes and recombinant CYP isoforms

Hyojin Kim, Kyung Ah Seo, Hyunmi Kim, Suk Lee Hye, Choong Hwan Lee, Jae Gook Shin, Kwang Hyeon Liu

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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 Clint values of hydroxy- and O-desmethyl-KR-32570 formation were similar to each other (0.03 vs 0.04 μL/min/pmol CYP, respectively). CYP3A4 mediated the formation of hydroxy-KR-32570 from KR-32570 with Clint = 0.24 μL/min/pmol CYP3A4. The intrinsic clearance for O-desmethyl-KR-32570 formation by CYP1A2 was 0.83 μL/min/pmol CYP1A2. These findings suggest that CYP3A4 and CYP1A2 enzymes are major enzymes contributing to the metabolism of KR-32570.

Original languageEnglish
Pages (from-to)469-474
Number of pages6
JournalArchives of Pharmacal Research
Volume30
Issue number4
DOIs
StatePublished - 30 Apr 2007

Keywords

  • Enzyme kinetics
  • KR-32570
  • LC/MS/MS
  • Microsomes

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