In vitro metabolism of a new cardioprotective agent, KR-33028 in the human liver microsomes and cryopreserved human hepatocytes

Hyojin Kim; Yune Jung Yoon; Hyunmi Kim; Eun Young Cha; Suk Lee Hye; Jeong Han Kim; Yang Yi Kyu; Sunkyung Lee; Gyeong Cheon Hyae; Sung Eun Yoo; Sang Seop Lee; Jae Gook Shin; Kwang Hyeon Liu

doi:10.1007/BF02978214

In vitro metabolism of a new cardioprotective agent, KR-33028 in the human liver microsomes and cryopreserved human hepatocytes

Hyojin Kim
, Yune Jung Yoon
, Hyunmi Kim
, Eun Young Cha
, Suk Lee Hye
, Jeong Han Kim
, Yang Yi Kyu
, Sunkyung Lee
, Gyeong Cheon Hyae
, Sung Eun Yoo
, Sang Seop Lee
, Jae Gook Shin
, Kwang Hyeon Liu

Inje University
Wonkwang University
Seoul National University
Korea Research Institute of Chemical Technology

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

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.

Original language	English
Pages (from-to)	1287-1292
Number of pages	6
Journal	Archives of Pharmacal Research
Volume	28
Issue number	11
DOIs	https://doi.org/10.1007/BF02978214
State	Published - Nov 2005

Keywords

Hepatocytes
KR-33028
LC/MS/MS
Metabolism
Microsomes

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10.1007/BF02978214

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Kim, H., Yoon, Y. J., Kim, H., Cha, E. Y., Hye, S. L., Kim, J. H., Kyu, Y. Y., Lee, S., Hyae, G. C., Yoo, S. E., Lee, S. S., Shin, J. G., & Liu, K. H. (2005). In vitro metabolism of a new cardioprotective agent, KR-33028 in the human liver microsomes and cryopreserved human hepatocytes. Archives of Pharmacal Research, 28(11), 1287-1292. https://doi.org/10.1007/BF02978214

@article{243694004b91436db44f86416d994afd,

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.",

keywords = "Hepatocytes, KR-33028, LC/MS/MS, Metabolism, Microsomes",

author = "Hyojin Kim and Yoon, \{Yune Jung\} and Hyunmi Kim and Cha, \{Eun Young\} and Hye, \{Suk Lee\} and Kim, \{Jeong Han\} and Kyu, \{Yang Yi\} and Sunkyung Lee and Hyae, \{Gyeong Cheon\} and Yoo, \{Sung Eun\} and Lee, \{Sang Seop\} and Shin, \{Jae Gook\} and Liu, \{Kwang Hyeon\}",

year = "2005",

month = nov,

doi = "10.1007/BF02978214",

language = "English",

volume = "28",

pages = "1287--1292",

journal = "Archives of Pharmacal Research",

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T1 - In vitro metabolism of a new cardioprotective agent, KR-33028 in the human liver microsomes and cryopreserved human hepatocytes

AU - Kim, Hyojin

AU - Yoon, Yune Jung

AU - Kim, Hyunmi

AU - Cha, Eun Young

AU - Hye, Suk Lee

AU - Kim, Jeong Han

AU - Kyu, Yang Yi

AU - Lee, Sunkyung

AU - Hyae, Gyeong Cheon

AU - Yoo, Sung Eun

AU - Lee, Sang Seop

AU - Shin, Jae Gook

AU - Liu, Kwang Hyeon

PY - 2005/11

Y1 - 2005/11

N2 - 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.

AB - 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.

KW - Hepatocytes

KW - KR-33028

KW - LC/MS/MS

KW - Metabolism

KW - Microsomes

UR - https://www.scopus.com/pages/publications/28844472543

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DO - 10.1007/BF02978214

M3 - Article

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AN - SCOPUS:28844472543

SN - 0253-6269

VL - 28

SP - 1287

EP - 1292

JO - Archives of Pharmacal Research

JF - Archives of Pharmacal Research

IS - 11

ER -

In vitro metabolism of a new cardioprotective agent, KR-33028 in the human liver microsomes and cryopreserved human hepatocytes

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Keywords

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