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Variability in Mass Spectrometry-based Quantification of Clinically Relevant Drug Transporters and Drug Metabolizing Enzymes
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. AstraZeneca R&D, Innovat Med & Early Dev Biotech Unit, Cardiovasc & Metab Dis, S-43150 Molndal, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
AstraZeneca R&D, Innovat Med & Early Dev Biotech Unit, Cardiovasc & Metab Dis, S-43150 Molndal, Sweden..
Max Planck Inst Biochem, Dept Prote & Signal Transduct, Biochem Prote Grp, D-82152 Martinsried, Germany..
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2017 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, no 9, p. 3142-3151Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC , 2017. Vol. 14, no 9, p. 3142-3151
Keyword [en]
drug transporters, drug metabolizing enzymes, membrane proteins, protein quantification, targeted proteomics, label-free proteomics
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-335414DOI: 10.1021/acs.molpharmaceut.7b00364ISI: 000410005100027PubMedID: 28767254OAI: oai:DiVA.org:uu-335414DiVA, id: diva2:1163146
Funder
Swedish Research Council, 2822, 5715
Available from: 2017-12-06 Created: 2017-12-06 Last updated: 2018-01-13Bibliographically approved

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