이 연구의 목적은 새로운 가역적 프로톤 펌프 억제제 KR-60436의 쥐와 사람 간 microsome에서 대사 경로를 규명하는 것과 KR-60436의 in vitro 대사에 관여하는 cytocome P450(CYP) 효소를 확인하는 것과 CYP 효소에 미치는 영향을 연구하는 것이다. 쥐 또는 사람 간 microsome에서 반응한 결과 KR-60436은 7 가지의 대사물을 생성한다. M3, M4, M5와 M6는 각각 O-demethyl-KR-60436, O-demethyl-pyrrole-KR-60436, N-dehydroxyethyl-KR-60436 과 pyrrole-KR-60436으로 인증된 ...
이 연구의 목적은 새로운 가역적 프로톤 펌프 억제제 KR-60436의 쥐와 사람 간 microsome에서 대사 경로를 규명하는 것과 KR-60436의 in vitro 대사에 관여하는 cytocome P450(CYP) 효소를 확인하는 것과 CYP 효소에 미치는 영향을 연구하는 것이다. 쥐 또는 사람 간 microsome에서 반응한 결과 KR-60436은 7 가지의 대사물을 생성한다. M3, M4, M5와 M6는 각각 O-demethyl-KR-60436, O-demethyl-pyrrole-KR-60436, N-dehydroxyethyl-KR-60436 과 pyrrole-KR-60436으로 인증된 표준물질을 LC/MS/MS를 이용한 분석을 바탕으로 규명하였다. M1, M2 와 M7 은 monohydroxylated-KR-60436, monohydroxylated-pyrrole-KR-60436와 N-dehydroxyethyl-pyrrole-KR-60436으로 임시적으로 규명하였다. 세가지 유형 사람 간 microsme에서 pyrrole-KR-60436, O-demethyl-KR-60436, O-demethyl-pyrrole-KR-60436와 N-dehydroxyethyl-KR-60436의 각각의 intrinsic clearance파라미터는 25.4, 8.7, 12.2 와 1.1 ㎕/mg proein/min을 나타낸다. 사람 간 microsme에서 dihydropyrrole 산화와 O-demethylation은 KR-60436의 대사에서 주요한 경로이며, N-dealkylation은 보다 작은 경로임을 말 수 있었다. 사람 간 microsome에서 KR-60436의 dihydropyrrole 산화와 O-demethylation, N-dealkylation에 관여하는 효소를 CYP효소가 발현된 microsome 대사와 화학억제제 실험과 immunoinhibition을 이용하여 규명하였다. pyrrole-KR-60436, O-demethyl-pyrrole-KR-60436와 N-dehydroxyethyl-KR-60436은 CYP3A4에 의해서 우세하게 대사 되고 또한 O-demethyl-KR-60436은 CYP2C9에 의해 대사 되며, CYP3A4와 2D6는 보다 적게 관여함을 알 수 있었다. 그러므로 KR-60436은 CYP3A4를 억제하거나 유도할 수 있는 약물과의 상호작용에 의해서 대사가 달라질 수 있거나 KR-60436의 약동력학이 변할 수 있다. 사람 간 시료에서 CYP2C9이 발현된 것은 KR-60436의 약동력학에 개별적인 차이를 줄 수 있다. KR-60436은 caffeine N3-demethylase의 강력한 억제제임을 발견하였다. KR-60436은 CYP2C8, CYP2C9, CYP2C19와 CYP2D6은 각각의 IC_(50) 30μM, 16μM, 13μM와 62μ 억제한다. CYP2A6, 2E1와 3A4는 영향을 미치지 않는다. CYP2C8, CYP2C9, CYP2C19 와 CYP2D6에 선택적인 기질의 대사에 영향을 줄 수 있는 KR-60436의 농도는 in vivo에서 도달하기 어려운 농도이다. 그러므로 KR-60436 유도된 약물과의 상호작용에서 CYP1A2에 의해서 대사되는 약물은 제외되야한다.
이 연구의 목적은 새로운 가역적 프로톤 펌프 억제제 KR-60436의 쥐와 사람 간 microsome에서 대사 경로를 규명하는 것과 KR-60436의 in vitro 대사에 관여하는 cytocome P450(CYP) 효소를 확인하는 것과 CYP 효소에 미치는 영향을 연구하는 것이다. 쥐 또는 사람 간 microsome에서 반응한 결과 KR-60436은 7 가지의 대사물을 생성한다. M3, M4, M5와 M6는 각각 O-demethyl-KR-60436, O-demethyl-pyrrole-KR-60436, N-dehydroxyethyl-KR-60436 과 pyrrole-KR-60436으로 인증된 표준물질을 LC/MS/MS를 이용한 분석을 바탕으로 규명하였다. M1, M2 와 M7 은 monohydroxylated-KR-60436, monohydroxylated-pyrrole-KR-60436와 N-dehydroxyethyl-pyrrole-KR-60436으로 임시적으로 규명하였다. 세가지 유형 사람 간 microsme에서 pyrrole-KR-60436, O-demethyl-KR-60436, O-demethyl-pyrrole-KR-60436와 N-dehydroxyethyl-KR-60436의 각각의 intrinsic clearance 파라미터는 25.4, 8.7, 12.2 와 1.1 ㎕/mg proein/min을 나타낸다. 사람 간 microsme에서 dihydropyrrole 산화와 O-demethylation은 KR-60436의 대사에서 주요한 경로이며, N-dealkylation은 보다 작은 경로임을 말 수 있었다. 사람 간 microsome에서 KR-60436의 dihydropyrrole 산화와 O-demethylation, N-dealkylation에 관여하는 효소를 CYP효소가 발현된 microsome 대사와 화학억제제 실험과 immunoinhibition을 이용하여 규명하였다. pyrrole-KR-60436, O-demethyl-pyrrole-KR-60436와 N-dehydroxyethyl-KR-60436은 CYP3A4에 의해서 우세하게 대사 되고 또한 O-demethyl-KR-60436은 CYP2C9에 의해 대사 되며, CYP3A4와 2D6는 보다 적게 관여함을 알 수 있었다. 그러므로 KR-60436은 CYP3A4를 억제하거나 유도할 수 있는 약물과의 상호작용에 의해서 대사가 달라질 수 있거나 KR-60436의 약동력학이 변할 수 있다. 사람 간 시료에서 CYP2C9이 발현된 것은 KR-60436의 약동력학에 개별적인 차이를 줄 수 있다. KR-60436은 caffeine N3-demethylase의 강력한 억제제임을 발견하였다. KR-60436은 CYP2C8, CYP2C9, CYP2C19와 CYP2D6은 각각의 IC_(50) 30μM, 16μM, 13μM와 62μ 억제한다. CYP2A6, 2E1와 3A4는 영향을 미치지 않는다. CYP2C8, CYP2C9, CYP2C19 와 CYP2D6에 선택적인 기질의 대사에 영향을 줄 수 있는 KR-60436의 농도는 in vivo에서 도달하기 어려운 농도이다. 그러므로 KR-60436 유도된 약물과의 상호작용에서 CYP1A2에 의해서 대사되는 약물은 제외되야한다.
1. The purposes of this study were to identify the metabolic pathway of a new H+/K+ ATPase inhibitor, KR-60436 [1-(4-methoxy-2-methyl-phenyl)-4-[(2- hydroxyethyl)amino]-6-trifluoromethoxy-2,3-dihydropyrrolo[3,2-c]quinoline] in rat and human liver microsomes, to characterize cytochrome P450 (CYP) enz...
1. The purposes of this study were to identify the metabolic pathway of a new H+/K+ ATPase inhibitor, KR-60436 [1-(4-methoxy-2-methyl-phenyl)-4-[(2- hydroxyethyl)amino]-6-trifluoromethoxy-2,3-dihydropyrrolo[3,2-c]quinoline] in rat and human liver microsomes, to characterize cytochrome P450 (CYP) enzymes responsible for the in vitro metabolism of KR-60436 and to investigate the potential effects of KR-60436 on CYP enzymes. 2. Following the incubation with rat or human liver microsomes, KR-60436 produced seven metabolites, (M1-7). M3, M4, M5 and M6 were identified as O-demethyl-KR-60436, O-demethyl-pyrrole-KR-60436, N-dehydroxyethyl-KR-60436 and pyrrole-KR-60436, respectively, based on LC/MS/MS analysis with authentic standards. M1, M2 and M7 were tentatively identified as monohydroxylated-KR-60436, monohydroxylated-pyrrole-KR-60436 and N-dehydroxyethyl-pyrrole-KR-60436, respectively. 3. Intrinsic clearance (Clint) parameters for pyrrole-KR-60436, O-demethyl-KR-60436, O-domethylpyrrole-KR-60436 and N-hydroxyethyl-KR-60436 formation in three human liver microsomes were 25.4, 87, 12.2 and 1.11/mg protein/min, respectively, suggesting that dihydropyrrole oxidation and O-demethylation are major pathways for the metabolism of KR-60436 in human liver microsomes, whereas N-dealkylation is a minor pathway. 4. To identify the specific enzymes responsible for dihydropyrrole oxidation, O-demethylation and N-dealkylation of KR-60436 employed a combination of chemical inhibition, immunoinhibition in human liver microsomes and metabolism by expressed recombinant CYP enzymes. KR-60436 is metabolized predominantly by CYP3A4 to pyrrole-KR-60436, O-demethylpyrrole-KR-60436 and N-dehydroxyethyl-KR-60436 and is also converted to the active metabolite O-demethyl-KR-60436 by CYP2C9 with minor contributions of CYP3A4 and 2D6. Therefore, any co-administered drugs that can inhibit or induce CYP3A4 may alter the metabolism of KR-60436 and potentially lead to changes in the pharmacokinetics of KR-60436 in patients. Since CYP2C9 expression is polymorhic in human liver samples, there is the individual difference in pharmacokinetics of KR-60436. 5. KR-60436 was found to be a potent inhibitor of caffeine N3-demethylase(IC50 approx. 3M), suggesting that KR-60436 will alter the clearance of the substrates for CYP1A2. KR-60436 moderately inhibited CYP2CB, CYP2C9, CYP2C19 and CYP2D6 with IC50 of approx. 30M, 16M, 13M and 62M, respectively CYP2A6, 2E1 and 3A4 were not affected by the presence of KR-60436. The concentrations of KR-60436 required to influence the metabolism of substrates selective for CYP2C8, 2C9, 2C19 and 2D6, are unlikely to be achieved in vivo. Therefore, KR-60436-induced drug interactions are expected with drugs metabolized by CYP1A2.
1. The purposes of this study were to identify the metabolic pathway of a new H+/K+ ATPase inhibitor, KR-60436 [1-(4-methoxy-2-methyl-phenyl)-4-[(2- hydroxyethyl)amino]-6-trifluoromethoxy-2,3-dihydropyrrolo[3,2-c]quinoline] in rat and human liver microsomes, to characterize cytochrome P450 (CYP) enzymes responsible for the in vitro metabolism of KR-60436 and to investigate the potential effects of KR-60436 on CYP enzymes. 2. Following the incubation with rat or human liver microsomes, KR-60436 produced seven metabolites, (M1-7). M3, M4, M5 and M6 were identified as O-demethyl-KR-60436, O-demethyl-pyrrole-KR-60436, N-dehydroxyethyl-KR-60436 and pyrrole-KR-60436, respectively, based on LC/MS/MS analysis with authentic standards. M1, M2 and M7 were tentatively identified as monohydroxylated-KR-60436, monohydroxylated-pyrrole-KR-60436 and N-dehydroxyethyl-pyrrole-KR-60436, respectively. 3. Intrinsic clearance (Clint) parameters for pyrrole-KR-60436, O-demethyl-KR-60436, O-domethylpyrrole-KR-60436 and N-hydroxyethyl-KR-60436 formation in three human liver microsomes were 25.4, 87, 12.2 and 1.11/mg protein/min, respectively, suggesting that dihydropyrrole oxidation and O-demethylation are major pathways for the metabolism of KR-60436 in human liver microsomes, whereas N-dealkylation is a minor pathway. 4. To identify the specific enzymes responsible for dihydropyrrole oxidation, O-demethylation and N-dealkylation of KR-60436 employed a combination of chemical inhibition, immunoinhibition in human liver microsomes and metabolism by expressed recombinant CYP enzymes. KR-60436 is metabolized predominantly by CYP3A4 to pyrrole-KR-60436, O-demethylpyrrole-KR-60436 and N-dehydroxyethyl-KR-60436 and is also converted to the active metabolite O-demethyl-KR-60436 by CYP2C9 with minor contributions of CYP3A4 and 2D6. Therefore, any co-administered drugs that can inhibit or induce CYP3A4 may alter the metabolism of KR-60436 and potentially lead to changes in the pharmacokinetics of KR-60436 in patients. Since CYP2C9 expression is polymorhic in human liver samples, there is the individual difference in pharmacokinetics of KR-60436. 5. KR-60436 was found to be a potent inhibitor of caffeine N3-demethylase(IC50 approx. 3M), suggesting that KR-60436 will alter the clearance of the substrates for CYP1A2. KR-60436 moderately inhibited CYP2CB, CYP2C9, CYP2C19 and CYP2D6 with IC50 of approx. 30M, 16M, 13M and 62M, respectively CYP2A6, 2E1 and 3A4 were not affected by the presence of KR-60436. The concentrations of KR-60436 required to influence the metabolism of substrates selective for CYP2C8, 2C9, 2C19 and 2D6, are unlikely to be achieved in vivo. Therefore, KR-60436-induced drug interactions are expected with drugs metabolized by CYP1A2.
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