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首页> 外文期刊>British Journal of Clinical Pharmacology >Plasma extracellular nanovesicle (exosome)-derived biomarkers for drug metabolism pathways: a novel approach to characterize variability in drug exposure
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Plasma extracellular nanovesicle (exosome)-derived biomarkers for drug metabolism pathways: a novel approach to characterize variability in drug exposure

机译：血浆细胞外纳米粒子（外鼻肌）的药物代谢途径的生物标志物：一种新的含药暴露变异性的新方法

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Aims Demonstrate the presence of cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) proteins and mRNAs in isolated human plasma exosomes and evaluate the capacity for exosome-derived biomarkers to characterize variability in CYP3A4 activity. Methods The presence of CYP and UGT protein and mRNA in exosomes isolated from human plasma and HepaRG cell culture medium was determined by mass spectrometry and reverse transcription-polymerase chain reaction, respectively. The concordance between exosome-derived CYP3A4 biomarkers and midazolam apparent oral clearance (CL/F) was evaluated in a small proof-of-concept study involving six genotyped (CYP3A4 *1/*1 and CYP3A5 *3/*3) Caucasian males. Results Exosomes isolated from human plasma contained peptides and mRNA originating from CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 2 J2, 3A4 and 3A5, UGT 1A1, 1A3, 1A4, 1A6, 1A9, 2B4, 2B7, 2B10 and 2B15, and NADPH-cytochrome P450 reductase. Mean (95% confidence interval) exosome-derived CYP3A4 protein expression pre- and post-rifampicin dosing was 0.24 (0.2-0.28) and 0.42 (0.21-0.65) ng ml(-1) exosome concentrate. Mean (95% confidence interval) exosome CYP3A4 mRNA expression pre- and post-rifampicin dosing was 6.0 (1.1-32.7) and 48.3 (11.3-104) x 10(-11) 2(-Delta Delta Ct), respectively. R-2 values for correlations of exosome-derived CYP3A4 protein expression, CYP3A4 mRNA expression, and ex vivo CYP3A4 activity with midazolam CL/F were 0.905, 0.787 and 0.832, respectively. Conclusions Consistent strong concordance was observed between exosome-derived CYP3A4 biomarkers and midazolam CL/F. The significance of these results is that CYP3A4 is the drug-metabolizing enzyme of greatest clinical importance and variability in CYP3A4 activity is poorly described by existing precision dosing strategies.
机译：目的证明了细胞色素P450（CYP）和UDP-葡萄糖醛糖基糖基转移酶（UGT）蛋白质和MRNA在分离的人血浆外泌体中的存在，并评估外渗衍生的生物标志物的能力，以表征CYP3A4活性的变异性。方法通过质谱法测定来自人血浆和肝细胞培养基中分离的外泌体的CYP和UGT蛋白和mRNA的存在，分别由质谱和逆转录聚合酶链反应测定。在涉及六种基因分型的小型概念验证研究中评估外渗CYP3A4生物标志物和咪达唑仑表观口腔清除（CL / F之间的一致性（CYP3A4 * 1 / * 1和CYP3A5 * 3 / * 3）高加索男性。结果从人血浆中分离的外泌体含有来自CYP 1a2,2b6,2c8,2c9,2c19,2d6,2e1,2j2,3a4和3a5，1a4，1a6,1a3,1a4,2b4,2b，2b10的肽和mRNA的肽和mRNA和2B15，NADPH-细胞色素P450还原酶。平均值（95％置信区间）外出细胞体衍生的CYP3A4蛋白表达预先和后利用蛋白剂量为0.24（0.2-0.28）和0.42（0.21-0.65）Ng ml（-1）外孔浓缩物。平均值（95％置信区间）外出组CYP3A4 mRNA表达分别和后利普疫后剂量为6.0（1.1-32.7）和48.3（11.3-104）×10（-11）2（-Delta delta CT）。具有咪达唑仑Cl / F的外出组衍生的CYP3A4蛋白表达，CYP3A4 mRNA表达和离体CYP3A4活性的R-2值分别为0.905,0.787和0.832。结论外源性CYP3A4生物标志物和Midazolam Cl / F之间观察到一致的强大一致性。这些结果的重要性是CYP3A4是药物代谢酶的最大临床重要性和CYP3A4活性的可变性是通过现有的精确剂量策略描述的。

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