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Different Roles of Human Cytochrome P450 2C9 and 3A Enzymes in Diclofenac 4'- and 5-Hydroxylations Mediated by Metabolically Inactivated Human Hepatocytes in Previously Transplanted Chimeric Mice.
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2019-12-31 , DOI: 10.1021/acs.chemrestox.9b00446 Tomonori Miura 1 , Shotaro Uehara 1, 2 , Makiko Shimizu 1 , Norie Murayama 1 , Masahiro Utoh 1 , Hiroshi Suemizu 2 , Hiroshi Yamazaki 1
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2019-12-31 , DOI: 10.1021/acs.chemrestox.9b00446 Tomonori Miura 1 , Shotaro Uehara 1, 2 , Makiko Shimizu 1 , Norie Murayama 1 , Masahiro Utoh 1 , Hiroshi Suemizu 2 , Hiroshi Yamazaki 1
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To investigate the respective roles of cytochromes P450 2C9 and 3A in drug oxidation in human livers, the in vivo pharmacokinetics of S-warfarin and diclofenac were analyzed after intravenous administrations in chimeric mice that had been transplanted with human hepatocytes. P450 2C9 was metabolically inactivated in the humanized mice by orally pretreating them with tienilic acid. After intravenous administration of S-warfarin, a significant difference in the concentration-time profiles of the primary metabolite 7-hydroxywarfarin between untreated mice and mice treated with tienilic acid was observed. In contrast, there were no apparent differences in the profiles for S-warfarin between the treated and untreated groups. The mean values of the maximum concentrations (Cmax) and the areas under the plasma concentration versus time curves (AUCinfinity) for 7-hydroxywarfarin were significantly lower (22 and 16% of the untreated values, respectively) in the treated group. This presumably resulted from suppressed P450 2C9 activity in the primary oxidative metabolism in vivo in the treated group. After diclofenac administration, plasma levels of diclofenac, 5-hydroxydiclofenac, and diclofenac acylglucuronide were roughly similar in pretreated and untreated mice. However, the mean Cmax and AUCinfinity values for 4'-hydroxydiclofenac were significantly lower (38 and 53% of the untreated group, respectively) in the treated group. The reported value of ∼0.8 for the fraction of S-warfarin metabolized to 7-hydroxywarfarin mediated by P450 2C9 in in vitro systems was similar to the value implied by the present humanized-liver mouse model pretreated with tienilic acid in which the AUC of 7-hydroxywarfarin was reduced by 84%. In contrast, the fractions of diclofenac metabolized to 4'-hydroxydiclofenac in in vitro and in vivo experiments were inconsistent. These results suggested that humanized-liver mice orally treated with tienilic acid might constitute an in vivo model for metabolically inactivated P450 2C9 in human hepatocytes transplanted into chimeric mice. Moreover, diclofenac, a typical in vitro P450 2C9 probe substrate, was cleared differently in vitro and in humanized-liver mice in vivo.
中文翻译：
人类细胞色素P450 2C9和3A酶在先前移植的嵌合小鼠中由代谢失活的人类肝细胞介导的双氯芬酸4'和5-羟基氧化中的不同作用。
为了研究细胞色素P450 2C9和3A在人肝中药物氧化中的各自作用，在静脉内施用已移植人肝细胞的嵌合小鼠后，分析了S-华法林和双氯芬酸的体内药代动力学。P450 2C9在人源化小鼠中通过用亚硝酸对它们进行口服预处理而使其代谢失活。静脉内施用S-华法林后，未处理的小鼠和经苯乙二酸处理的小鼠之间的主要代谢物7-羟基华法林的浓度-时间曲线存在显着差异。相反，在治疗组和未治疗组之间，S-华法林的概况无明显差异。在治疗组中，7-羟基华法林的最大浓度平均值（Cmax）和血浆浓度-时间曲线下面积（AUCinfinity）明显较低（分别为未处理值的22％和16％）。推测这是由于治疗组体内体内主要氧化代谢中P450 2C9活性降低所致。双氯芬酸给药后，在预处理和未处理的小鼠中，双氯芬酸，5-羟基双氯芬酸和双氯芬酸酰基葡萄糖醛酸的血浆水平大致相似。但是，在治疗组中，4'-羟基双氯芬酸的平均Cmax和AUCinfinity值明显较低（分别为未治疗组的38％和53％）。报告值为〜0。在体外系统中，由P450 2C9介导的S-华法林的代谢成7-羟基华法林的分数的图8与本人源化肝小鼠模型经铁镍酸预处理所隐含的值相似，其中7-羟基华法林的AUC降低了84％。相反，在体外和体内实验中，双氯芬酸代谢成4'-羟基双氯芬酸的馏分不一致。这些结果表明，口服经亚硝酸处理的人源化肝小鼠可能构成了移植到嵌合小鼠中的人肝细胞中代谢失活的P450 2C9的体内模型。此外，双氯芬酸，一种典型的体外P450 2C9探针底物，在体外和在人源化肝小鼠体内的清除方式均不同。
更新日期：2019-12-31
中文翻译：
人类细胞色素P450 2C9和3A酶在先前移植的嵌合小鼠中由代谢失活的人类肝细胞介导的双氯芬酸4'和5-羟基氧化中的不同作用。
为了研究细胞色素P450 2C9和3A在人肝中药物氧化中的各自作用，在静脉内施用已移植人肝细胞的嵌合小鼠后，分析了S-华法林和双氯芬酸的体内药代动力学。P450 2C9在人源化小鼠中通过用亚硝酸对它们进行口服预处理而使其代谢失活。静脉内施用S-华法林后，未处理的小鼠和经苯乙二酸处理的小鼠之间的主要代谢物7-羟基华法林的浓度-时间曲线存在显着差异。相反，在治疗组和未治疗组之间，S-华法林的概况无明显差异。在治疗组中，7-羟基华法林的最大浓度平均值（Cmax）和血浆浓度-时间曲线下面积（AUCinfinity）明显较低（分别为未处理值的22％和16％）。推测这是由于治疗组体内体内主要氧化代谢中P450 2C9活性降低所致。双氯芬酸给药后，在预处理和未处理的小鼠中，双氯芬酸，5-羟基双氯芬酸和双氯芬酸酰基葡萄糖醛酸的血浆水平大致相似。但是，在治疗组中，4'-羟基双氯芬酸的平均Cmax和AUCinfinity值明显较低（分别为未治疗组的38％和53％）。报告值为〜0。在体外系统中，由P450 2C9介导的S-华法林的代谢成7-羟基华法林的分数的图8与本人源化肝小鼠模型经铁镍酸预处理所隐含的值相似，其中7-羟基华法林的AUC降低了84％。相反，在体外和体内实验中，双氯芬酸代谢成4'-羟基双氯芬酸的馏分不一致。这些结果表明，口服经亚硝酸处理的人源化肝小鼠可能构成了移植到嵌合小鼠中的人肝细胞中代谢失活的P450 2C9的体内模型。此外，双氯芬酸，一种典型的体外P450 2C9探针底物，在体外和在人源化肝小鼠体内的清除方式均不同。
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