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.
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.
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人细胞色素 P450 2C9 和 3A 酶在先前移植的嵌合小鼠中代谢失活的人肝细胞介导的双氯芬酸 4-和 5-羟基化中的不同作用。
DOI：
10.1021/acs.chemrestox.9b00446
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发表时间：
2020
影响因子：
4.1
通讯作者：
H.
中科院分区：
文献类型：
--
作者：
.Miura;T.;Uehara;S.;Shimizu;M.;Murayama;N.;Utoh;M.;Suemizu;H.;and Yamazaki;H.
为探讨细胞色素P4502C9和3A在人肝脏药物氧化中的作用，用人肝细胞移植的嵌合体小鼠静脉注射华法林和双氯芬酸，分析了它们在体内的药代动力学。在人源化小鼠中，口服替尼酸可使P4502C9代谢失活。静脉注射OFS-华法林后，未处理的小鼠和替尼酸处理的小鼠的主要代谢物7-羟基华法林的浓度-时间曲线有显著差异。相反，在治疗组和未治疗组之间，华法林的分布没有明显差异。治疗组7-羟华法林的最大血药浓度(Cmax)和血药浓度-时间曲线下面积(AUCinfinity)的平均值分别为未治疗组的22%和16%。这可能是由于治疗组体内初级氧化代谢酶P450 2C9活性受到抑制所致。在双氯芬酸给药后，双氯芬酸、5-羟基双氯芬酸和双氯芬酸酰基葡萄糖醛酸脂的血浆水平在治疗前和未治疗的小鼠中大致相似。但治疗组4‘-羟基双氯芬酸的Cmax和AUCinfinity值显著低于未治疗组(分别为未治疗组的38%和53%)。在体外系统中，P4502C9介导的7-羟基华法林代谢成7-羟基华法林的∼为0.8AUC值与目前用替尼酸处理的人源化小鼠肝模型的AUC值相似，其中7-羟基华法林的AUC值降低了84%。相比之下，双氯芬酸在体外和体内代谢为4‘-羟基双氯芬酸的级分不一致。这些结果提示，人肝细胞经替尼酸口服处理后，可能构成了人肝细胞代谢失活P450 2C9移植到嵌合体小鼠体内的活体模型。此外，双氯芬酸是一种典型的体外P450 2C9探针底物，在体外和在人肝小鼠体内均有不同程度的清除。
To investigate the respective roles of cytochromes P450 2C9 and 3A in drug oxidation in human livers, thein vivopharmacokinetics ofS-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 ofS-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 forS-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 metabolismin vivoin 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 meanCmaxand AUCinfinityvalues 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 ofS-warfarin metabolized to 7-hydroxywarfarin mediated by P450 2C9 inin vitrosystems 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 inin vitroandin vivoexperiments were inconsistent. These results suggested that humanized-liver mice orally treated with tienilic acid might constitute anin vivomodel for metabolically inactivated P450 2C9 in human hepatocytes transplanted into chimeric mice. Moreover, diclofenac, a typicalin vitroP450 2C9 probe substrate, was cleared differentlyin vitroand in humanized-liver micein vivo.
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影响因子：
1.8
作者：
Parmentier, Yannick;Pothier, Corinne;Walther, Bernard
通讯作者：
Walther, Bernard
影响因子：
3.4
作者：
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影响因子：
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作者：
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影响因子：
3.9
作者：
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影响因子：
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作者：
A. Wood;P. Bolli;H. Waal‐Manning;F. O. Simpson
通讯作者：
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