Murine Cyp3a knockout chimeric mice with humanized liver: prediction of the metabolic profile of nefazodone in humans.
Murine Cyp3a knockout chimeric mice with humanized liver: prediction of the metabolic profile of nefazodone in humans.
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具有人源化肝脏的小鼠 Cyp3a 敲除嵌合小鼠：预测奈法唑酮在人类中的代谢特征。
DOI：
10.1002/bdd.1990
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Usui T.
中科院分区：
文献类型：
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作者：
Nakada N;Kawamura A;Kamimura H;Sato K;Kazuki Y;Kakuni M;Ohbuchi M;Kato K;Tateno C;Oshimura M;Usui T.
采用人源化肝脏嵌合小鼠（PXB小鼠）研究了药物在人体内的代谢和药代动力学。然而，来自肝脏的残留小鼠酶活性和小鼠小肠代谢的存在会阻碍人类药物代谢的预测。近年来，研究人员开发了小鼠细胞色素p4503基因敲除人肝脏嵌合小鼠（Cyp3aKO CM）。为了评估对药物代谢的预测，以10 mg/kg的剂量口服奈法唑酮（NEF）给药以下小鼠品系：Cyp3aKO CM、小鼠cyp3agene敲除（Cyp3a KO）、PXB和严重联合免疫缺陷（SCID）小鼠。液相色谱-质谱法用于血浆、尿液和胆汁的代谢谱分析。对羟基奈法唑酮（OH‐NEF）、三唑二酮形式（TD）、间氯苯哌嗪和烷基代谢物inCyp3aKO CM的预测结果优于inCyp3aKO、PXB或SCID小鼠。此外，NEF、OH - NEF和TD的临床暴露水平在yp3ako CM中重现。相比之下，NEF在PXB和SCID小鼠中迅速代谢为TD，而在inCyp3aKO小鼠中则没有，这表明小鼠CYP3A参与了这些小鼠NEF的消除。这些发现表明NEF inCyp3aKO CM的代谢谱与PXB小鼠的代谢谱在定性和定量上有所不同，这是由于NEF及其代谢物通过小鼠CYP3A的代谢率更高。因此，recyp3ako CM可能有助于预测人类候选药物的代谢谱。版权所有©2016 John Wiley & Sons， Ltd。
Chimeric mice with humanized livers (PXB mice) are used to investigate the metabolism and pharmacokinetics of drugs in humans. However, residual murine enzymatic activities derived from the liver and the presence of mouse small intestinal metabolism can hamper the prediction of human drug metabolism. Recently murineCytochrome P450 3agene knockout chimeric mice with humanized livers (Cyp3aKO CM) were developed. To evaluate the prediction of drug metabolism, nefazodone (NEF) was administered orally at 10 mg/kg to the following mouse strains:Cyp3aKO CM, murineCyp3agene knockout (Cyp3a KO), PXB and severe combined immunodeficiency (SCID) mice. Liquid chromatography‐mass spectrometry was used for metabolic profiling of plasma, urine and bile. The prediction of human metabolite levels such as hydroxy nefazodone (OH‐NEF), triazoledione form (TD),m‐chlorophenylpiperazine and dealkyl metabolites inCyp3aKO CM was superior to that inCyp3aKO, PXB or SCID mice. Further, clinical exposure levels of NEF, OH‐NEF and TD were reproduced inCyp3aKO CM. In contrast, NEF was rapidly metabolized to TD in both PXB and SCID mice but not inCyp3aKO mice, suggesting that murine CYP3A is involved in the elimination of NEF in these mice. These findings demonstrate that the metabolic profile of NEF inCyp3aKO CM differs qualitatively and quantitatively from that in PXB mice due to the higher metabolic rate of NEF and its metabolites via murine CYP3A. ThereforeCyp3aKO CM might be useful in predicting the metabolic profiles of drug candidates in humans. Copyright © 2016 John Wiley & Sons, Ltd.