In vitro metabolism of a new cardioprotective agent, KR-33028 in the human liver microsomes and cryopreserved human hepatocytes.
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.
Kim
Hyojin
H
Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 614-735, Korea.
Yoon
Yune-Jung
YJ
Kim
Hyunmi
H
Cha
Eun-Young
EY
Lee
Hye Suk
HS
Kim
Jeong-Han
JH
Yi
Kyu Yang
KY
Lee
Sunkyung
S
Cheon
Hyae Gyeong
HG
Yoo
Sung-Eun
SE
Lee
Sang-Seop
SS
Shin
Jae-Gook
JG
Liu
Kwang-Hyeon
KH
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*
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