During pharmacotherapy, knowledge about the actual drug and metabolite concentrations in plasma is often critical. Individual dose adjustments can be performed based on pre-emptive genotyping of certain absorption, distribution, metabolism, and excretion (ADME) genes but also using therapeutic drug monitoring (TDM). Analyses of liquid biopsies for tumor-derived components are well-established and have been found to be a good complement to biopsy examinations. Recently, liquid biopsy-based quantification of cell-free RNA (cfRNA) in plasma exosomes was proposed as a proxy measurement for the expression of different hepatic ADME genes and for the rate of drug metabolism, constituting an alternative to TDM. In this study, we validated these findings by examining the correlation between mRNA expression of eight different CYP genes in liver and the corresponding rate of enzyme-specific drug metabolism in 96 donor-matched liver samples. Analyses of CYP-dependent drug metabolism in liver microsomes in comparison to the level of mRNA expression for the different CYP genes revealed a mean Pearson correlation coefficient of 0.28. The highest correlations (0.33–0.34) were obtained for CYP2D6 and CYP3A4 and the weakest correlations were observed for CYP1A2 and CYP2B6 (0.18–0.21). In all cases, the correlations obtained were too weak to demonstrate a predictive relationship, likely due to different regulatory and post-translational events controlling the rate of enzyme activity. Our results reinforce the notion that, whilst liquid biopsy-based approaches might have utility for prediction of hepatic CYP protein expression, they are not currently an important substitute for TDM.

中文翻译：

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用于 CYP 活性谱测定的液体活检或治疗药物监测

在药物治疗期间，了解血浆中的实际药物和代谢物浓度通常至关重要。可以根据某些吸收、分布、代谢和排泄 (ADME) 基因的先发制人基因分型，以及使用治疗药物监测 (TDM) 来进行个体剂量调整。对肿瘤衍生成分的液体活检分析已经很成熟，并且已被发现是对活检检查的良好补充。最近，提出了基于液体活检的血浆外泌体中游离 RNA (cfRNA) 定量作为不同肝脏 ADME 基因表达和药物代谢速率的替代测量，构成了 TDM 的替代方法。在这项研究中，我们通过检查肝脏中八种不同 CYP 基因的 mRNA 表达与 96 个供体匹配的肝脏样本中相应的酶特异性药物代谢率之间的相关性来验证这些发现。与不同 CYP 基因的 mRNA 表达水平相比，肝微粒体中 CYP 依赖性药物代谢的分析显示平均皮尔逊相关系数为 0.28。CYP2D6 和 CYP3A4 的相关性最高 (0.33–0.34)，而 CYP1A2 和 CYP2B6 (0.18–0.21) 的相关性最弱。在所有情况下，获得的相关性都太弱而无法证明预测关系，这可能是由于控制酶活性速率的不同调节和翻译后事件。我们的结果强化了这样的观念，