• Archives of Pharmacal Research
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• v.27 no.2
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• pp.239-245
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• 2004

KR-31543, (2S,3R,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(2 -methyl-2H-tetrazol-5-ylmethyl) amino]-3,4-dihydro-2-dimethoxymethyl-3-hydroxy-2-methyl-2H-1-benzopyran, is a new neuroprotective agent for preventing ischemia-reperfusion damage. This study was performed to identify the metabolic pathway of KR-31543 in human liver microsomes and to characterize cytochrome P450 (CYP) enzymes that are involved in the metabolism of KR-31543. Human liver microsomal incubation of KR-31543 in the presence of NADPH resulted in the formation of two metabolites, M1 and M2. M1 was identified as N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine on the basis of LC/MS/MS analysis with a synthesized authentic standard, and M2 was suggested to be hydroxy-KR-31543. Correlation analysis between the known CYP enzyme activities and the rates of the formation of M 1 and M2 in the 12 human liver microsomes have showed significant correlations with testosterone 6$\beta$-hydroxylase activity (a marker of CYP3A4). Ketoconazole, a selective inhibitor of CYP3A4, and anti-CYP3A4 monoclonal antibodies potently inhibited both N-hydrolysis and hydroxylation of KR-31543 in human liver microsomes. These results provide evidence that CYP3A4 is the major isozyme responsible for the metabolism of KR-31543 to M1 and M2.

• Archives of Pharmacal Research
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• v.25 no.5
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• pp.664-668
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• 2002

KR-31543,(2S,3R,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3,4-dihydro-2-dimethoxymethyl-3-hydroxy-2-methyl-2H-1-benzopyran is a new neuroprotetive agent for ischemia-reperfusion damage. The in vitro and in vivo metabolism of KR-31543 in rats has been studied by LC-electrospray mass spectrometry. Rat liver microsomal incubation of KR-31543 in the presence of NADPH resulted in the formation of a metabolite M1. M1 was identified as N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine on the basis of LC-MS/MS analysis with the synthesized authentic standard. Rat CYP3A1 and 3A2 are the major CYP isozymes involved in the formation of M1.

• Proceedings of the PSK Conference
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• 2003.04a
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• pp.286.2-287
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• 2003

The purpose of this paper was to identify the metabolic pathway of a new neuroprotective agent, KR-31543 for ischemia-reperfusion damage in human liver microsomes and characterize cytochrome P450 (CYP) enzymes involved in the in vitro metabolism of KR-31543 generates two metabolites in human liver microsomes : M1, N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine and M2, hydroxy-KR-31543. (omitted)

• Proceedings of the PSK Conference
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• 2003.04a
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• pp.312.2-313
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• 2003

The purpose of this study was to report dose-independent pharmacokinetics of KR-31543, a new neuroprotective agent for ischemia-reperfusion damage, after intravenous and oral administration and first-pass effects after intravenous. intraportal, intragastric, and intraduodenal administration in rats. After intravenous (10, 20 and 50 mg/kg) and oral (10, 20 and 50 mg/kg) administration, the pharmacokinetic parameters of KR-31543 were dose-independent. (omitted)

• Archives of Pharmacal Research
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• v.25 no.5
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• pp.647-651
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• 2002

An LC/MS/MS method for the simultaneous determination of a neuroprotective agent for ischemia-reperfusion damage, KR-31378 and its N-acetyl metabolite KR-31612 in human plasma was developed. KR-31378, KR-31612 and the internal standard. KR-31543 were extracted from human plasma by liquid-liquid extraction. A reverse-phase HPLC separation was performed on Luna phenylhexyl column with the mixture of acetonitrile-5 mM ammonium formate (55:45, v/v) as mobile phase. The detection of analytes was performed using an electrospray ionization tandem mass spectrometry in the multiple reaction monitoring mode. The lower limits of quantification for KR-31378 and KR-31612 were 2.0 ng/ml. The method showed a satisfactory sensitivity, precision, accuracy, recovery and selectivity.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.217.2-217.2
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• 2003

A liquid chromatography-tandem mass spectrometric (LC/MS/MS) method was developed for the determination of a new anti-angiogenic drug KR-31831 in rat plasma. KR-31831 and internal standard, KR-31543 were extracted from rat plasma with dichloromethane at basic pH. A reverse-phase LC separation was performed on Luna C8 column with the mixture of acetonitrile-ammonium formate (10 mM, pH 4.5) (67:33, v/v) as mobile phase. The detection of analytes was performed using an electrospray ionization tandem mass spectrometry in the multiple-reaction-monitoring mode. (omitted)

• Proceedings of the PSK Conference
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• 2001.10a
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• pp.306.2-307
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• 2001