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KMID : 0043320050280111287
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Archives of Pharmacal Research
2005 Volume.28 No. 11 p.1287 ~ p.1292
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In Vitro Metabolism of a New Cardioprotective Agent, KR-33028 in the Human Liver Microsomes and Cryopreserved Human Hepatocytes
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Kim Hyo-Jin
Yoon Yune-Jung
Kim Hyun-Mi
Cha Eun-Young
Lee Hye-Suk
Kim Jeong-Han
Yi Kyu-Yang
Lee Sun-Kyung
Cheon Hyae-Gyeong
Yoo Sung-Eun
Lee Sang-Seop
Shin Jae-Kook
Liu Kwang-Hyeon
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Abstract
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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, KR33028 was found to inhibit moderately the metabolism of CYP1A2 substrates. Based on the results obtained metabolic pathway of KR-33028 is proposed.
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KEYWORD
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KR-33028, Metabolism, Microsomes, Hepatocytes, LC/MS/MS
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