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细胞色素P450变异对哌替啶脱甲基生成神经毒性代谢物去甲哌替啶的影响。

Impact of cytochrome P450 variation on meperidine -demethylation to the neurotoxic metabolite normeperidine.

作者信息

Murray Jessica L, Mercer Susan L, Jackson Klarissa D

机构信息

Department of Pharmaceutical Sciences, Lipscomb University College of Pharmacy and Health Sciences, Nashville, TN, USA.

Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.

出版信息

Xenobiotica. 2020 Feb;50(2):209-222. doi: 10.1080/00498254.2019.1599465. Epub 2019 Apr 24.

Abstract
  1. Meperidine is an opioid analgesic that undergoes demethylation to form the neurotoxic metabolite normeperidine. Previous studies indicate that meperidine -demethylation is catalyzed by cytochrome P450 2B6 (CYP2B6), CYP3A4, and CYP2C19.2. The purpose of this study was to examine the relative P450 contributions to meperidine -demethylation and to evaluate the effect of polymorphism on normeperidine generation. Experiments were performed using recombinant P450 enzymes, selective chemical inhibitors, enzyme kinetic assays, and correlation analysis with individual -genotyped human liver microsomes.3. The catalytic efficiency (/) for meperidine -demethylation was similar between recombinant CYP2B6 and CYP2C19, but markedly lower by CYP3A4.4. In -genotyped human liver microsomes, normeperidine formation was significantly correlated with CYP2C19 activity (-mephenytoin 4-hydroxylation).5. CYP2C19 inhibitor (+)--3-benzylnirvanol and CYP3A inhibitor ketoconazole significantly reduced microsomal normeperidine generation by an individual donor with high CYP2C19 activity, whereas donors with lower CYP2C19 activity were sensitive to inhibition by ketoconazole but not benzylnirvanol.6. These findings demonstrate that the relative CYP3A4, CYP2B6, and CYP2C19 involvement in meperidine -demethylation depends on the enzyme activities in individual human liver microsomal samples. CYP2C19 is likely an important contributor to normeperidine generation in individuals with high CYP2C19 activity, but additional factors influence inter-individual metabolite accumulation.
摘要
  1. 哌替啶是一种阿片类镇痛药,可通过去甲基化形成神经毒性代谢产物去甲哌替啶。先前的研究表明,哌替啶的去甲基化由细胞色素P450 2B6(CYP2B6)、CYP3A4和CYP2C19催化。

  2. 本研究的目的是检查细胞色素P450对哌替啶去甲基化的相对贡献,并评估基因多态性对去甲哌替啶生成的影响。使用重组P450酶、选择性化学抑制剂、酶动力学测定以及与个体基因分型的人肝微粒体进行相关性分析来开展实验。

  3. 重组CYP2B6和CYP2C19对哌替啶去甲基化的催化效率(/)相似,但CYP3A4的催化效率明显较低。

  4. 在个体基因分型的人肝微粒体中,去甲哌替啶的形成与CYP2C19活性(-美芬妥因4-羟化)显著相关。

  5. CYP2C19抑制剂(+)- - 3-苄基尼凡诺和CYP3A抑制剂酮康唑可显著降低具有高CYP2C19活性的个体供体微粒体中去甲哌替啶的生成,而CYP2C19活性较低的供体对酮康唑的抑制敏感,但对苄基尼凡诺不敏感。

  6. 这些发现表明,CYP3A4、CYP2B6和CYP2C19参与哌替啶去甲基化的相对程度取决于个体人肝微粒体样品中的酶活性。CYP2C19可能是CYP2C19活性高的个体中去甲哌替啶生成的重要贡献者,但其他因素会影响个体间代谢产物的积累。

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