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

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

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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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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

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SN - 0253-6269

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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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