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  • 1.
    Hammer, H. S.
    et al.
    Univ Tubingen, Nat Wissensch & Med Inst, Reutlingen, Germany..
    Poetz, O.
    Univ Tubingen, Nat Wissensch & Med Inst, Reutlingen, Germany..
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Wegler, Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Development of MS- based immunoassays for Cytochrome P450 and transporter quantification2016In: Naunyn-Schmiedeberg's Archives of Pharmacology, ISSN 0028-1298, E-ISSN 1432-1912, Vol. 389, no 1, p. S47-S47Article in journal (Other academic)
  • 2.
    Karlgren, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Science for Life Laboratory.
    Simoff, Ivailo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Backlund, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Science for Life Laboratory.
    Wegler, Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. AstraZeneca.
    Keiser, Markus
    Department of Clinical Pharmacology, Center of Drug Absorption and Transport, University Medicine of Greifswald, Greifswald, Germany..
    Handin, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Müller, Janett
    Department of Clinical Pharmacology, Center of Drug Absorption and Transport, University Medicine of Greifswald, Greifswald, Germany..
    Lundquist, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Jareborg, Anne-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Oswald, Stefan
    Department of Clinical Pharmacology, Center of Drug Absorption and Transport, University Medicine of Greifswald, Greifswald, Germany..
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Science for Life Laboratory.
    A CRISPR-Cas9 Generated MDCK Cell Line Expressing Human MDR1 Without Endogenous Canine MDR1 (cABCB1): An Improved Tool for Drug Efflux Studies.2017In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 106, no 9, p. 2909-2913Article in journal (Refereed)
    Abstract [en]

    Madin-Darby canine kidney (MDCK) II cells stably transfected with transport proteins are commonly used models for drug transport studies. However, endogenous expression of especially canine MDR1 (cMDR1) confounds the interpretation of such studies. Here we have established an MDCK cell line stably overexpressing the human MDR1 transporter (hMDR1; P-glycoprotein), and used CRISPR-Cas9 gene editing to knockout the endogenous cMDR1. Genomic screening revealed the generation of a clonal cell line homozygous for a 4-nucleotide deletion in the canine ABCB1 gene leading to a frameshift and a premature stop codon. Knockout of cMDR1 expression was verified by quantitative protein analysis and functional studies showing retained activity of the human MDR1 transporter. Application of this cell line allowed unbiased reclassification of drugs previously defined as both substrates and non-substrates in different studies using commonly used MDCK-MDR1 clones. Our new MDCK-hMDR1 cell line, together with a previously developed control cell line, both with identical deletions in the canine ABCB1 gene and lack of cMDR1 expression represent excellent in vitro tools for use in drug discovery.

  • 3.
    Mateus, André
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Treyer, Andrea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Wegler, Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. AstraZeneca R&D, Cardiovasc & Metab Dis Innovat Med, DMPK, SE-43183 Molndal, Sweden..
    Karlgren, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Matsson, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Intracellular drug bioavailability: a new predictor of system dependent drug disposition2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, p. 1-12, article id 43047Article in journal (Refereed)
    Abstract [en]

    Intracellular drug exposure is influenced by cell-and tissue-dependent expression of drug-transporting proteins and metabolizing enzymes. Here, we introduce the concept of intracellular bioavailability (F-ic) as the fraction of extracellular drug available to bind intracellular targets, and we assess how Fic is affected by cellular drug disposition processes. We first investigated the impact of two essential drug transporters separately, one influx transporter (OATP1B1; SLCO1B1) and one efflux transporter (P-gp; ABCB1), in cells overexpressing these proteins. We showed that OATP1B1 increased Fic of its substrates, while P-gp decreased Fic. We then investigated the impact of the concerted action of multiple transporters and metabolizing enzymes in freshly-isolated human hepatocytes in culture configurations with different levels of expression and activity of these proteins. We observed that Fic was up to 35-fold lower in the configuration with high expression of drug-eliminating transporters and enzymes. We conclude that Fic provides a measurement of the net impact of all cellular drug disposition processes on intracellular bioavailable drug levels. Importantly, no prior knowledge of the involved drug distribution pathways is required, allowing for high-throughput determination of drug access to intracellular targets in highly defined cell systems (e.g., single-transporter transfectants) or in complex ones (including primary human cells).

  • 4.
    Wegler, Christine
    et al.
    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..
    Gaugaz, Fabienne Z.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Andersson, Tommy B.
    AstraZeneca R&D, Innovat Med & Early Dev Biotech Unit, Cardiovasc & Metab Dis, S-43150 Molndal, Sweden..
    Wisniewsk, Jacek R.
    Max Planck Inst Biochem, Dept Prote & Signal Transduct, Biochem Prote Grp, D-82152 Martinsried, Germany..
    Busch, Diana
    Univ Med Greifswald, Dept Clin Pharmacol, Ctr Drug Absorpt & Transport, D-17489 Greifswald, Germany..
    Gröer, Christian
    Univ Med Greifswald, Dept Clin Pharmacol, Ctr Drug Absorpt & Transport, D-17489 Greifswald, Germany..
    Oswald, Stefan
    Univ Med Greifswald, Dept Clin Pharmacol, Ctr Drug Absorpt & Transport, D-17489 Greifswald, Germany..
    Norén, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Weiss, Frederik
    Univ Tubingen, NMI Nat & Med Sci Inst, D-72770 Reutlingen, Germany..
    Hammer, Helen S.
    Univ Tubingen, NMI Nat & Med Sci Inst, D-72770 Reutlingen, Germany..
    Joos, Thomas O.
    Univ Tubingen, NMI Nat & Med Sci Inst, D-72770 Reutlingen, Germany..
    Poetz, Oliver
    Univ Tubingen, NMI Nat & Med Sci Inst, D-72770 Reutlingen, Germany..
    Achour, Brahim
    Univ Manchester, Ctr Appl Pharmacokinet Res, Manchester M13 9PL, Lancs, England..
    Rostami-Hodjegan, Amin
    Univ Manchester, Ctr Appl Pharmacokinet Res, Manchester M13 9PL, Lancs, England..
    van de Steeg, Evita
    TNO, Netherlands Org Appl Sci Res, NL-3700 AJ Zeist, Netherlands..
    Wortelboer, Heleen M.
    TNO, Netherlands Org Appl Sci Res, NL-3700 AJ Zeist, Netherlands..
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Variability in Mass Spectrometry-based Quantification of Clinically Relevant Drug Transporters and Drug Metabolizing Enzymes2017In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, no 9, p. 3142-3151Article in journal (Refereed)
    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.

  • 5.
    Wegler, Christine
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Gaugaz, Fabienne Z.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Andersson, Tommy B.
    AstraZeneca R&D, Cardiovasc & Metab Dis iMed DMPK, Molndal, Sweden..
    Wisniewski, Jacek R.
    Max Planck Inst Biochem, Dept Prote & Signal Transduct, Martinsried, Germany..
    Busch, Diana
    Univ Med Greifswald, Ctr Drug Absorpt & Transport C DAT, Greifswald, Germany..
    Oswald, Stefan
    Univ Med Greifswald, Ctr Drug Absorpt & Transport C DAT, Dept Pharmacol & Clin Pharmacol, Greifswald, Germany..
    Weiss, Frederik
    Univ Tubingen, NMI Nat & Med Sci Inst, Tubingen, Germany..
    Hammer, Helen
    Univ Tubingen, NMI Nat & Med Sci Inst, Tubingen, Germany..
    Joos, Thomas O.
    Univ Tubingen, NMI Nat & Med Sci Inst, Tubingen, Germany..
    Poetz, Oliver
    Univ Tubingen, NMI Nat & Med Sci Inst, Tubingen, Germany..
    Wortelboer, Heleen M.
    TNO, Zeist, Netherlands..
    van de Steeg, Evita
    TNO, Zeist, Netherlands..
    Achour, Brahim
    Univ Manchester, Manchester Pharm Sch, Ctr Appl Pharmacokinet Res, Manchester, Lancs, England..
    Rostami, Amin
    Univ Manchester, Manchester Pharm Sch, Ctr Appl Pharmacokinet Res, Manchester, Lancs, England..
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Protein quantification of human hepatic drug transporters and metabolizing enzymes: an inter-laboratory and methodological comparison2016In: Drug metabolism reviews (Softcover ed.), ISSN 0360-2532, E-ISSN 1097-9883, Vol. 48, p. 98-98Article in journal (Other academic)
  • 6.
    Weiss, Frederik
    et al.
    Univ Tubingen, NMI Nat & Med Sci Inst, Markwiesenstr 55, D-72770 Reutlingen, Germany;SIGNATOPE GmbH, Reutlingen, Germany.
    Hammer, Helen S.
    Univ Tubingen, NMI Nat & Med Sci Inst, Markwiesenstr 55, D-72770 Reutlingen, Germany;SIGNATOPE GmbH, Reutlingen, Germany.
    Klein, Kathrin
    Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany;Univ Tubingen, Dept Clin Pharmacol, Tubingen, Germany.
    Planatscher, Hannes
    Univ Tubingen, NMI Nat & Med Sci Inst, Markwiesenstr 55, D-72770 Reutlingen, Germany;SIGNATOPE GmbH, Reutlingen, Germany.
    Zanger, Ulrich M.
    Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany;Univ Tubingen, Dept Clin Pharmacol, Tubingen, Germany.
    Norén, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Wegler, Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Innovat Med & Early Dev Biotech Unit, Cardiovasc & Metab Dis, Molndal, Sweden.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Joos, Thomas O.
    Univ Tubingen, NMI Nat & Med Sci Inst, Markwiesenstr 55, D-72770 Reutlingen, Germany;SIGNATOPE GmbH, Reutlingen, Germany.
    Poetz, Oliver
    Univ Tubingen, NMI Nat & Med Sci Inst, Markwiesenstr 55, D-72770 Reutlingen, Germany;SIGNATOPE GmbH, Reutlingen, Germany.
    Direct Quantification of Cytochromes P450 and Drug Transporters-A Rapid, Targeted Mass Spectrometry-Based Immunoassay Panel for Tissues and Cell Culture Lysates2018In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 46, no 4, p. 387-396Article in journal (Refereed)
    Abstract [en]

    The quantification of drug metabolizing enzymes and transporters has recently been revolutionized on the basis of targeted proteomic approaches. Isotope-labeled peptides are used as standards for the quantification of the corresponding proteins in enzymatically fragmented samples. However, hurdles in these approaches are low throughput and tedious sample prefractionation steps prior to mass spectrometry (MS) readout. We have developed an assay platform using sensitive and selective immunoprecipitation coupled with mass spectrometric readout allowing the quantification of proteins directly from whole cell lysates using less than 20,000 cells per analysis. Peptide group-specific antibodies (triple X proteomics antibodies) enable the enrichment of proteotypic peptides sharing a common terminus. These antibodies were employed to establish a MS-based immunoassay panel for the quantification of 14 cytochrome P450 (P450) enzymes and nine transporters. We analyzed the P450 enzyme and transporter levels in genotyped liver tissue homogenates and microsomes, and in samples from a time course induction experiment in human hepatocytes addressing different induction pathways. For the analysis of P450 enzymes and transporters only a minute amount of sample is required and no prefractionation is necessary, thus the assay platform bears the potential to bridge cell culture model experiments and results from whole organ tissue studies.

1 - 6 of 6
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