Variability in Mass Spectrometry-based Quantification of Clinically Relevant Drug Transporters and Drug Metabolizing Enzymes,Molecular Pharmaceutics

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Variability in Mass Spectrometry-based Quantification of Clinically Relevant Drug Transporters and Drug Metabolizing Enzymes
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2017-08-16 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b00364
Christine Wegler _{1,

2} , Fabienne Z. Gaugaz ₁ , Tommy B. Andersson ₂ , Jacek R. Wiśniewski ₃ , Diana Busch ₄ , Christian Gröer ₄ , Stefan Oswald ₄ , Agneta Norén ₅ , Frederik Weiss ₆ , Helen S. Hammer ₆ , Thomas O. Joos ₆ , Oliver Poetz ₆ , Brahim Achour ₇ , Amin Rostami-Hodjegan ₇ , Evita van de Steeg ₈ , Heleen M. Wortelboer ₈ , Per Artursson ₁

Affiliation

Many different methods are used for mass-spectrometry-based protein quantification in pharmacokinetics and systems pharmacology. It has not been established to what extent the results from these various methods are comparable. Here, we compared six different mass spectrometry-based proteomics methods by measuring the expression of clinically relevant drug transporters and metabolizing enzymes in human liver. Mean protein concentrations were in general quantified to similar levels by methods using whole tissue lysates. Methods using subcellular membrane fractionation gave incomplete enrichment of the proteins. When the enriched proteins were adjusted to levels in whole tissue lysates, they were on average 4-fold lower than those quantified directly in whole tissue lysates. The differences in protein levels were propagated into differences in predictions of hepatic clearance. In conclusion, caution is needed when comparing and applying quantitative proteomics data obtained with different methods, especially since membrane fractionation is common practice for protein quantification used in drug clearance predictions.

中文翻译：

基于质谱的临床相关药物转运蛋白和药物代谢酶定量的变异性

在药代动力学和系统药理学中，许多不同的方法用于基于质谱的蛋白质定量。尚不确定这些各种方法的结果在何种程度上具有可比性。在这里，我们通过测量人肝中临床相关药物转运蛋白和代谢酶的表达，比较了六种基于质谱的蛋白质组学方法。通常通过使用全组织裂解物的方法将平均蛋白质浓度定量至相似的水平。使用亚细胞膜分级分离的方法未完全富集蛋白质。当将富集的蛋白质调整到整个组织裂解物中的水平时，它们平均比直接在整个组织裂解物中定量的蛋白质低4倍。蛋白质水平的差异传播为肝清除率预测的差异。总之，在比较和应用通过不同方法获得的定量蛋白质组学数据时，需要特别小心，特别是因为膜分离是药物清除率预测中使用的蛋白质定量的常规做法。

更新日期：2017-08-16

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