Identification of Enzymes Responsible for the N-Oxidation of Darexaban Glucuronide, the Pharmacologically Active Metabolite of Darexaban, and the Glucuronidation of Darexaban N-Oxides in Human Liver Microsomes
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概要
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Darexaban maleate is a novel oral direct factor Xa inhibitor. Darexaban glucuronide (YM-222714) was the major component in plasma after oral administration of darexaban to humans and is the pharmacologically active metabolite. Additionally, YM-222714 N-oxides were detected as minor metabolites in human plasma and urine. It is possible that YM-222714 N-oxides are formed by the N-oxidation of YM-222714 and/or the glucuronidation of darexaban N-oxides (YM-542845) in vivo. The former reaction is the pharmacological inactivation process. In this study, we identified the human enzymes responsible for YM-222714 N-oxidation and the uridine 5′-diphosphate (UDP)-glucuronosyltransferase (UGT) isoforms involved in YM-542845 glucuronidation in vitro. YM-222714 N-oxidation activity was detected in human liver microsomes (HLM), but not in human intestinal microsomes. In HLM, YM-222714 N-oxidation activities were significantly correlated with flavin-containing monooxygenase (FMO) marker enzyme activities (p<0.001) and inhibited by methimazole, a typical inhibitor of FMOs. Recombinant human FMO3 and FMO1 were capable of efficiently catalyzing YM-222714 N-oxidation, but not FMO5 or any recombinant human cytochrome P450 (CYP) isoforms. Considering the mRNA expression levels of FMO isoforms in human liver, these results strongly suggest that YM-222714 N-oxidation in HLM is mainly catalyzed by FMO3. In HLM, YM-542845 glucuronidation was strongly inhibited by typical substrates for UGT1A8, UGT1A9, and UGT1A10. Recombinant human UGT1A7, UGT1A8, UGT1A9, and UGT1A10 were capable of catalyzing YM-542845 glucuronidation, and UGT1A9 exhibited the highest intrinsic clearance. Considered together with the expression levels of UGT isoforms in human liver, these results strongly suggest that YM-542845 glucuronidation in HLM is mainly catalyzed by UGT1A9.
著者
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SUZUKI Katsuhiro
Drug Metabolism Laboratories, Drug Development Division, Yamanouchi Pharmaceutical Co., Ltd.
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IWATSUBO Takafumi
Drug Metabolism Laboratories, Institute for Drug Development Research, Yamanouchi Pharmaceutical Co.
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SHIRAGA Toshifumi
Drug Metabolism Research Laboratories, Astellas Pharma Inc.
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Usui Takashi
Drug Metabolism Laboratories Drug Development Division Yamanouchi Pharmaceutical Co. Ltd.
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Hashimoto Tadashi
Drug Metabolism Laboratories Drug Development Division Yamanouchi Pharmaceutical Co. Ltd.
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Yajima Kanako
Pharmacokinetics And Bioanalysis Center Shin Nippon Biomedical Laboratories Ltd.
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Teragaki Takuya
Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd.
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Miyashita Aiji
Drug Metabolism Research Laboratories, Drug Discovery Research, Astellas Pharma Inc.
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Shiraga Toshifumi
Drug Metabolism Research Laboratories, Drug Discovery Research, Astellas Pharma Inc.
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Iwatsubo Takafumi
Drug Metabolism Research Laboratories, Drug Discovery Research, Astellas Pharma Inc.
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Hashimoto Tadashi
Drug Metabolism Research Laboratories, Drug Discovery Research, Astellas Pharma Inc.
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Usui Takashi
Drug Metabolism Research Laboratories, Drug Discovery Research, Astellas Pharma Inc.
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