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  • 1.
    Andersson, Patrik
    et al.
    AstraZeneca R&D, Mölndal, Sweden.
    Kenne, Kerstin
    AstraZeneca R&D, Södertälje, Sweden.
    Glinghammar, Björn
    AstraZeneca R&D, Södertälje, Sweden.
    Pointon, Amy V.
    Global Safety Assessment AstraZeneca, Macclesfield, United Kingdom.
    Åkerblad, Peter
    CVGI iMed AstraZeneca, Mölndal, Sweden.
    Lutz, Mareike
    CVGI iMed AstraZeneca, Mölndal, Sweden.
    Hovdal, Daniel
    CVGI iMed AstraZeneca, Mölndal, Sweden.
    Maxvall, Ingela
    CVGI iMed AstraZeneca, Mölndal, Sweden.
    Lindstedt, Eva-Lotte
    CVGI iMed AstraZeneca, Mölndal, Sweden.
    Toxicity with LXR agonists – Problem solving activities for mechanistic understanding2012Inngår i: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, nr Suppl. (S), s. S39-S39Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Several lines of evidence points toward the potential positive effects of LXR (Liver X Receptor) modulators for effective and safe therapy of cardiovascular diseases (CVDs). LXR is a dimeric nuclear hormone receptor that exists as a combination of RXR and one of two subtypes LXR alpha or beta, which act as cholesterol sensors. LXR alpha is highly expressed in the liver, intestine and adipose tissue while LXR beta is ubiquitously expressed. Activation of LXR up-regulates several genes involved in reverse cholesterol transport (RCT), including ABC transporters. This results in increased efflux of cholesterol from macrophages in atherosclerotic vascular lesions to the circulation and further on to other tissues to ultimately be excreted into the faeces. These effects together with systemic and local anti-inflammatory properties of LXR modulation are likely to contribute to decreased atherosclerosis. The positive effects of LXR activation on RCT and cholesterol balance must be obtained without negative lipid effects, since LXR also activates lipogenic genes. Other types of toxicity and approaches to better understand the mechanism(s) behind these will be presented. Copyright © 2012 Published by Elsevier Ireland Ltd.

  • 2.
    Burestedt, E.
    et al.
    Department of Analytical Chemistry, University of Lund, Lund, Sweden.
    Emnéus, J.
    Department of Analytical Chemistry, University of Lund, Lund, Sweden.
    Gorton, L.
    Department of Analytical Chemistry, University of Lund, Lund, Sweden.
    Marko-Varga, G.
    Department of Analytical Chemistry, University of Lund, Lund, Sweden.
    Domínguez, E.
    Department of Analytical Chemistry, Faculty of Pharmacy, University of Alcalá de Henares, Alcalá de Henares, Spain.
    Ortega, F.
    Department of Analytical Chemistry, Faculty of Pharmacy, University of Alcalá de Henares, Alcalá de Henares, Spain.
    Narváez, A.
    Department of Analytical Chemistry, Faculty of Pharmacy, University of Alcalá de Henares, Alcalá de Henares, Spain.
    Irth, H.
    Division of Analytical Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands.
    Lutz, Mareike
    Division of Analytical Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands.
    Puig, D.
    Department of Environmental Chemistry, CID-CSIC, Barcelona, Spain.
    Barceló, D.
    Department of Environmental Chemistry, CID-CSIC, Barcelona, Spain.
    Optimisation and validation of an automated solid phase extraction technique coupled on-line to enzyme-based biosensor detection for the determination of phenolic compounds in surface water samples1995Inngår i: Chromatographia, ISSN 0009-5893, E-ISSN 1612-1112, Vol. 41, nr 3-4, s. 207-215Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A fully integrated screening system for phenolic compounds was developed incorporating on-line solid phase extraction, fractionation and biosensor detection. Two different types of biosensors, solid graphite and carbon paste electrodes incorporating the enzyme tyrosinase, were compared and used in the screening system. Interfacing of the solid phase extraction and fractionation with the biosensor detection was given special attention since the biosensors were not compatible with the organic modifier used for desorption of phenols from the solid phase extraction step. The system was validated with conventional analytical techniques. Surface water samples from the Ebro river were spiked with 1,10, and 25μg L−1 of catechol, phenol,p-cresol, respectively. Three out of seven samples were spiked and the correct samples were identified, containing phenols equivalent to the spiked concentrations. © 1995 Friedr. Vieweg & Sohn Verlagsgesellschaft mbH.

  • 3.
    Desbans, Coraline
    et al.
    KaLy-Cell, Plobsheim, France.
    Hilgendorf, Constanze
    UCB Pharma S.A, Braine-l'Alleud, Belgium.
    Lutz, Mareike
    Högskolan i Halmstad.
    Bachellier, P
    Centre de Chirurgie Viscérale et de Transplantation, Hôpital de Hautepierre, Strasbourg, France.
    Zacharias, T
    Service de Chirurgie Viscérale et Digestive, Centre Hospitalier Emile Muller-Moenchsberg, Mulhouse, France.
    Weber, JC
    Clinique de l'Orangerie, Strasbourg, France.
    Dolgos, Hugues
    UCB Pharma S.A, Braine-l'Alleud, Belgium.
    Richert, Lysiane
    KaLy-Cell, Plobsheim, France.
    Ungell, Anna-Lena
    UCB Pharma S.A, Braine-l'Alleud, Belgium.
    Prediction of fraction metabolized via CYP3A in humans utilizing cryopreserved human hepatocytes from a set of 12 single donors2014Inngår i: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 44, nr 1, s. 17-27Artikkel i tidsskrift (Fagfellevurdert)
  • 4.
    Desbans, Coraline
    et al.
    KaLy Cell, Illkirch-Graffenstaden, France.
    Hilgendorf, Constanze
    AstraZeneca R&D, DMPK and Bioanalytical Chemistry, Mölndal, Sweden.
    Richert, Lysiane
    KaLy Cell, Illkirch-Graffenstaden, France.
    Lutz, Mareike
    AstraZeneca R&D, DMPK and Bioanalytical Chemistry, Mölndal, Sweden.
    Ungell, Anna-Lena
    AstraZeneca R&D, DMPK and Bioanalytical Chemistry, Mölndal, Sweden.
    Accurate prediction of variability in CLint and Fm via 3A4 is only obtained by assessing a series of individual cryopreserved human hepatocyte batches2010Inngår i: Drug metabolism reviews (Softcover ed.), ISSN 0360-2532, E-ISSN 1097-9883, Vol. 42, nr Suppl. 1, s. 274-274Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Multiple in-vitro and in-vivo methods are currently assessed and under discussion to predict human clearance and pharmacokinetics from preclinical studies. A combination of high fm with a high fraction metabolism via a single pathway, e.g. via CYP3A4 (fmCYP3A4), has been recognized as a high risk factor for Drug Drug Interactions (DDI) in the clinical setting[1],[2],[3],[4] . Thus, an early predictive tool to allow for appropriate modeling of this potential risk for DDI is highly warranted. Hepatocytes, capable of both phase I and phase II reactions, are an attractive system to study fraction metabolized (fm) via a single pathway. In the present study, intrinsic clearance (CLint) was determined in cryopreserved human hepatocytes in suspension for a set of five compounds with known and variable fm via CYP3A4 (amitriptyline, loratadine, methylprednisolone, midazolam, and tacrolimus) in the absence or presence of ketoconazole. In order to get an insight into the influence of inter-individual variability, twelve batches of cryopreserved human hepatocytes with either high, moderate or low CYP3A4-dependent activity towards midazolam (MDZ) were chosen. Clint values were determined as substrate depletion under shaking conditions (900rpm) using an elliptic shaker as previously reported[5]. For all compounds, the mean CLint for individual donors in absence of ketoconazole correlated very well with literature data on the mean of individual donors1,2,3, and/or pools of donors5. Average fmCYP3A4 for midazolam was 83%, tacrolimus 64%, methylprednisolone 55%, amitriptyline 28%, and loratadine 19% are also well within the literature data2,3,4. Interestingly, the results obtained for a homogenous subpopulation regarding MDZ CLint and percent inhibition by ketoconazole, were not directly related to the ketoconazole sensitive CLint for the other CYP3A4 substrates tested. The variability in CYP3A4 contribution for compounds having multiple metabolic pathways cannot be predicted by the fm3A4 for MDZ. This suggests that an overall prediction of CLint or fm via CYP3A4 for compounds partially metabolized by this enzyme is not possible. Thus, the individual differences in CLint for a given compound and fmCYPi can only be well covered by assessing a series of individual cryopreserved human hepatocyte batches.

    [1] Lu, C., Miwa, G. T., Prakash, S. R., Gan, L-S. and Balani, S. K. (2007), Drug Metabolism And Disposition, 35: 1, 79–85

    [2] Lu, C., Hatsis,P., Berg,C., Lee, F. W. and Balani, S. K. (2008), Drug Metabolism And Disposition, 36: 7, 1255–1260

    [3] Lu, C., Hatsis,P., Berg,C., Lee, F. W. and Balani, S. K. (2008), Drug Metabolism And Disposition, 36: 7, 1261–1266

    [4] Emoto, C., Murase, S. and Iwasaki, K.(2006), Xenobiotica, 36: 8, 671 — 683

    [5] Simon ,S., Blanchard, N., Alexandre, E., Hewitt, N. J., Bachellier, P., Heyd, B., Coassolo, P., Schuler, F., Richert, L., (2009) ‘MV-HUF Copenhagen’

  • 5.
    Johannesson, Petra
    et al.
    Cardiovascular & Metabolic Diseases Innovative Medicines Unit, AstraZeneca R&D Mölndal, Mölndal, Sweden.
    Bratt, Emma
    Cardiovascular & Metabolic Diseases Innovative Medicines Unit, AstraZeneca R&D Mölndal, Mölndal, Sweden.
    Broo, Anders
    Cardiovascular & Metabolic Diseases Innovative Medicines Unit, AstraZeneca R&D Mölndal, Mölndal, Sweden.
    Evertsson, Emma
    Cardiovascular & Metabolic Diseases Innovative Medicines Unit, AstraZeneca R&D Mölndal, Mölndal, Sweden.
    Judkins, Robert
    Cardiovascular & Metabolic Diseases Innovative Medicines Unit, AstraZeneca R&D Mölndal, Mölndal, Sweden.
    Leandersson, Carina
    Cardiovascular & Metabolic Diseases Innovative Medicines Unit, AstraZeneca R&D Mölndal, Mölndal, Sweden.
    Lutz, Mareike
    Cardiovascular & Metabolic Diseases Innovative Medicines Unit, AstraZeneca R&D Mölndal, Mölndal, Sweden.
    Pemberton, Nils
    Cardiovascular & Metabolic Diseases Innovative Medicines Unit, AstraZeneca R&D Mölndal, Mölndal, Sweden.
    Swanson, Marianne
    Cardiovascular & Metabolic Diseases Innovative Medicines Unit, AstraZeneca R&D Mölndal, Mölndal, Sweden.
    Westerlund, Kristina
    Cardiovascular & Metabolic Diseases Innovative Medicines Unit, AstraZeneca R&D Mölndal, Mölndal, Sweden.
    Åkerblad, Peter
    Cardiovascular & Metabolic Diseases Innovative Medicines Unit, AstraZeneca R&D Mölndal, Mölndal, Sweden.
    Lindstedt, Eva-Lotte
    Cardiovascular & Metabolic Diseases Innovative Medicines Unit, AstraZeneca R&D Mölndal, Mölndal, Sweden.
    SAR and optimization of trioxoisothiazole-based liver receptor X (LXR) agonists leading to the clinical candidate AZD39712014Inngår i: Division of Medicinal Chemistry: Scientific Abstracts for the 248th National Meeting and Exposition: August 10-14, 2014: San Francisco, CA, 2014, Vol. 248, s. 247-247Konferansepaper (Fagfellevurdert)
    Abstract [en]

    The liver X receptors (LXRα and LXRβ) are members of the nuclear receptor family of transcription factors. The activation of LXR induces genes involved in reverse cholesterol transport (RCT), which is believed to be the main effect of LXR agonists in the prevention or treatment of atherosclerosis. However LXR agonists have also been shown to cause hepatic steatosis and hypertriglyceridaemia. The ability to separate beneficial effects from negative effects has been a challenge that so far has hampered the development of LXR agonists for human use. We herein describe the SAR and optimization of a series of trioxoisothiazole-based LXR agonists leading to compounds with nanomolar potencies and a separation of beneficial versus negative effects in vivo. This work ultimately led to the nomination of AZD3971 as a candidate for the treatment of atherosclerosis.

  • 6.
    Larsson, Marita
    et al.
    DMPK and Bioanalytical Chemistry, AstraZeneca R&D Mölndal, Mölndal, Sweden.
    Lutz, Mareike
    DMPK and Bioanalytical Chemistry, AstraZeneca R&D Mölndal, Mölndal, Sweden.
    Transient isotachophoresis for sensitivity enhancement in capillary electrophoresis-mass spectrometry for peptide analysis2000Inngår i: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 21, nr 14, s. 2859-2865Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Transient isotachophoresic (ITP) focusing was used for the on-line analysis of peptides by capillary zone electrophoresis-mass spectrometry (CZE-MS), allowing injection volumes of up to 0.9 microL. A sheath liquid electrospray interface was used with a single quadrupole mass analyzer. First, the technique was applied to the qualitative analysis of a tryptic digest of cytochrome c, resulting in low-background, high-quality spectra. Second, the linear range was investigated by selected ion monitoring (SIM) for a peptidomimetic direct thrombin inhibitor melagatran (Mr 429.5) and two endogenous peptides, substance P (Mr 1348) and calcitonin gene-related peptide (alpha-CGRP; Mr 3806).

  • 7.
    Lutz, Mareike
    et al.
    Division of Analytical Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden, Netherlands.
    Burestedt, Elisabeth
    Department of Analytical Chemistry, University of Lund, Lund, Sweden.
    Emnéus, Jenny
    Department of Analytical Chemistry, University of Lund, Lund, Sweden.
    Lidén, Helena
    Department of Analytical Chemistry, University of Lund, Lund, Sweden.
    Gobhadi, Shahpar
    Department of Analytical Chemistry, University of Lund, Lund, Sweden.
    Gorton, Lo
    Department of Analytical Chemistry, University of Lund, Lund, Sweden.
    Marko-Varga, György
    Department of Analytical Chemistry, University of Lund, Lund, Sweden.
    Effects of different additives on a tyrosinase based carbon paste electrode1995Inngår i: Analytica Chimica Acta, ISSN 0003-2670, E-ISSN 1873-4324, Vol. 305, nr 1-3, s. 8-17Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The influence of a number of solid and chemical additives on the sensitivity and operational stability of a tyrosinase carbon paste electrode was studied. Cyclic voltammograms were run of the electrochemically active catechol/o-quinone couple on unmodified and additive modified carbon paste electrodes without tyrosinase. This was done in order to study the influence of these additives on the pure electrochemistry of the carbon paste. The influence on the total system (additive and enzyme modified carbon paste electrode) was studied in the flow injection mode. In some instances a dramatic improvement of the direct electron transfer of the catechol/o-quinone couple was obtained with both solid and chemical additives included in the carbon paste. A similar improvement of biosensor sensitivity in the flow injection mode was obtained with most chemical additives whereas the solid additives had a negative impact on biosensor sensitivity. The results obtained in this work indicate that these additives influence the purely electrochemical processes at the carbon paste and/or the performance of the enzyme in the carbon paste environment. How and why these additives can possibly influence the biosensor performance are discussed. © 1995.

  • 8.
    Lutz, Mareike
    et al.
    Division of Analytical Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
    Dominguez, Elena
    Department of Analytical Chemistry, Faculty of Pharmacy, University of Alcalá de Henares, Alcalá de Henares (Madrid), Spain.
    Development and Optimization of a Solid Composite Tyrosinase Biosensor for Phenol Detection in Flow Injection Systems1996Inngår i: Electroanalysis, ISSN 1040-0397, E-ISSN 1521-4109, Vol. 8, nr 2, s. 117-123Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Bulk-modified epoxy-graphite tyrosinase biosensors were fabricated by four different procedures. The influence of these fabrication procedures on the analytical performance of the enzyme electrode in an amperometric wall-jet flow cell has been studied. The bioprobe performance is assessed by cyclic voltammetry. Higher current densities and narrower peaks were obtained when the enzyme was introduced in the dry state into the epoxy-graphite material, instead of introducing it previously dissolved in the buffer. In the FI system responses of 11.79 μA cm-2 and 1.43 μA cm-2 are then obtained for catechol and phenol respectively for 50 μL injections of 20 μM solutions. Moreover, if gold/palladium is introduced into the epoxy-graphite, a further increase in current is achieved resulting in 27.70 μA cm-2 and 4.90 μA cm-2 for catechol and phenol, respectively. This biosensor can operate in aqueous as well as in mixed aqueous-organic environments.

  • 9.
    Lutz, Mareike
    et al.
    Division of Analytical Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
    Irth, Hubertus
    Division of Analytical Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
    Tjaden, Ubbo R.
    Division of Analytical Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
    van der Greef, Jan
    Division of Analytical Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
    Applying hollow fibres for separating free and bound label in continuous-flow immunochemical detection1996Inngår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 755, nr 2, s. 179-187Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    On-line liquid chromatography-immunochemical detection (LC-ICD) provides the possibility to individually monitor cross-reactive compounds overcoming the need of tedious fraction collection. ICD is performed as a post-column reaction detection system and is based on a two-step immunoreaction. In the first step unlabelled antibodies are added to the LC effluent and allowed to react with antigens (analytes) eluting from the LC column. The amount of analytes bound to the antibodies is measured by adding, in a second step, labelled antigen to the reaction mixture. For quantitation, free and bound label need to be separated prior to detection. The present paper describes a hollow fibre module (HFM), which can be used for this purpose. Separation of free and bound label occurs on discrimination by size. Using biotin as a model compound, a detection limit of 30 nmol/l can be reached employing anti-biotin antibodies and a low-molecular-mass fluorescence label in the LC-ICD system. Additional to low-molecular-mass labels, the HFM allows the use of small enzyme labels. In this context, horseradish peroxidase-labelled biotin was used as a label in combination with antibodies in the immunochemical detection of biotin. This allows future implementation of commercially available enzyme immunoassay kits in continuous-flow immunochemical detection.

  • 10.
    Lutz, Mareike
    et al.
    Division of Analytical Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
    Irth, Hubertus
    Division of Analytical Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
    Tjaden, Ubbo R.
    Division of Analytical Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
    van der Greef, Jan
    Division of Analytical Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
    Biochemical detection for direct bead surface analysis1997Inngår i: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 69, nr 23, s. 4878-4884Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A continuous-now biochemical detection system is presented which recognizes biologically active compounds immobilized to solid phases. This approach can be used to screen, for example, solid-phase combinatorial libraries for lead compounds. Biochemical detection is performed by mixing a plug of a solid-phase suspension with labeled affinity protein, During a short reaction time, the labeled affinity protein will only bind to ligands, i.e., compounds with biological activity. Hereafter, the free and bound labels are separated by means of a hollow fiber module, Quantitation of the free label is performed with a conventional now-through fluorescence detector, Total assay time amounts to less than 3 min. Biochemical detection for direct bead surface analysis was developed for two model systems. The first model system used fluorescence-labeled avidin as affinity protein and its ligands biotin and iminobiotin immobilized to agarose as analytes. The second model system used fluorescence-labeled antisheep (Fab)(2) fragments as affinity protein and different IgGs immobilized to agarose as analytes. The feasibility of this approach for recognition of solid-phase immobilized ligands was documented by screening 50 samples with a 100% hit rate.

  • 11.
    Lutz, Mareike
    et al.
    Division of Analytical Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, Netherlands.
    Irth, Hubertus
    Division of Analytical Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, Netherlands.
    Tjaden, Ubbo R.
    Division of Analytical Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, Netherlands.
    van der Greef, Jan
    Division of Analytical Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, Netherlands.
    Implementation of affinity solid-phases in continuous-flow biochemical detection1997Inngår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 776, nr 2, s. 169-178Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A continuous-flow biochemical detection system is presented which allows the use of solid-phase immobilised affinity proteins. The biochemical detection is performed by mixing analyte with a labelled ligand followed by the addition of solid-phase immobilised affinity protein. After a reaction time of 85 s, free and bound label are separated by means of a hollow fibre module. Quantitation of the free label is performed with a conventional flow-through fluorescence detector. Total assay time amounts to less than 2 min. Biotin was chosen as the model compound using a range of streptavidin-coated solid-phases and an antibody-coated solid-phase as affinity material, and fluorescein–biotin as low-molecular-mass label. The relative standard deviation for twenty repetitive injections was 10.9%. A calibration curve was constructed in the concentration range between 20 and 400 nmol l−1 leading to a correlation coefficient of 0.994. A limit of detection of 8 nmol l−1 was obtained. © 1997 Elsevier Science B.V.

  • 12.
    Lutz, Mareike
    et al.
    Bioanalytical Chemistry, Astra Hässle AB, Mölndal, Sweden.
    Larsson, Marita
    Bioanalytical Chemistry, Astra Hässle AB, Mölndal, Sweden.
    On-Line Microdialysis-Electrospray Mass Spectrometry for Automated Desalting of Small-Volume Peptide Samples1999Inngår i: Chromatographia, ISSN 0009-5893, E-ISSN 1612-1112, Vol. 49, nr Suppl. 1, s. S28-S34Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Electrospray ionization mass spectrometry (ESI-MS) is an important tool for biomolecule analysis. Because the salt content of small-volume peptide samples can hamper analyte ionization, such samples require treatment before ESI-MS.The approach described here consists in interfacing ESI-MS with on-line microdialysis which affords rapid desalting and buffer-exchange. On-line microdialysis was performed by means of a hollow fiber (i.d. 200 μm) coupled to fused silica capillaries. Peptide samples were introduced into the capillary flow system as plugs and transferred to the dialysis cell and the electrospray by means of hydrodynamic pressure. As a result, the ionization efficiency of peptidic analytes was increased and adduct formation with, e.g., sodium, was reduced owing to reduced levels of nonvolatile salts. The feasibility of on-line microdialysis-ESI-MS is shown with a proteolytic digest originating from two-dimensional gel electrophoresis.

  • 13.
    Lutz, Mareike
    et al.
    DMPK & Bioanalytical Chemistry, AstraZeneca R&D Mölndal, Mölndal, Sweden.
    Markling, Magnus E.
    DMPK & Bioanalytical Chemistry, AstraZeneca R&D Mölndal, Mölndal, Sweden.
    Masimirembwa, Collen M.
    DMPK & Bioanalytical Chemistry, AstraZeneca R&D Mölndal, Mölndal, Sweden.
    Monolithic silica rod liquid chromatography with ultraviolet or fluorescence detection for metabolite analysis of cytochrome P450 marker reactions2002Inngår i: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 780, nr 2, s. 205-215Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In vitro cytochrome P450 assays are used in metabolism studies in support of early phases of drug discovery to investigate, e.g., metabolic stability, enzyme inhibition and induction by new chemical entities. LC-UV and LC-fluorescence are traditional analytical tools in support of such studies. However, these tools typically comprise different methods of relatively low throughput for the various metabolites of probe reactions. In recent years, LC-MS methods have been developed to increase throughput. Increased throughput can also be achieved by means of modern chromatographic tools in combination with UV and fluorescence detection. This approach is especially suitable when cytochrome P450 isoforms are investigated by means of single probe incubations. Here, an LC-UV/fluorescence system based on a monolithic porous silica column is described for the analysis of metabolites of nine cytochrome P450 marker reactions [phenacetin to paracetamol (CYP1A2), coumarin to 7-hydroxycoumarin (CYP2A6), paclitaxel to 6alpha-hydroxypaclitaxel (CYP2C8), diclofenac to 4-hydroxydiclofenac (CYP2C9), mephenytoin to 4-hydroxymephenytoin (CYP2C19), bufuralol to 1-hydroxybufuralol (CYP2D6), chlorzoxazone to 6-hydroxychlorzoxazone (CYP2E1), midazolam to 1-hydroxymidazolam (CYP3A4), and testosteron to 6beta-hydroxytestosteron (CYP3A4)]. While offering sensitivities and linear ranges comparable to previously reported methods, the set-up described here provides ease of use and increased throughput with maximum cycle times of 4.5 min. © 2002 Elsevier Science B.V. All rights reserved.

  • 14.
    Lutz, Mareike
    et al.
    Division of Analytical Chemistry, Leiden/Amsterdam Ctr. for Drug Res., Leiden University, Leiden, Netherlands.
    Oosterkamp, Aaike J.
    Division of Analytical Chemistry, Leiden/Amsterdam Ctr. for Drug Res., Leiden University, Leiden, Netherlands.
    Irth, Hubertus
    Division of Analytical Chemistry, Leiden/Amsterdam Ctr. for Drug Res., Leiden University, Leiden, Netherlands.
    On-line Coupling of Liquid Chromatography to Biological Assays1997Inngår i: Chimica oggi, ISSN 0392-839X, E-ISSN 1973-8250, Vol. 15, nr 1-2, s. 11-15Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Combining two powerful technologies - liquid chromatography and bioassays results in analytical methodologies which are characterised by high selectivity and sensitivity. In contrast to microtitre-type bioassays, biochemical reactions proceed in a closed, continuous-flow reaction detection system coupled directly to the outlet of the chromatographic separation column. The interaction of substances eluting from the separation column with molecular targets such as antibodies or receptors is monitored directly overcoming tedious fraction collection and manual operations required to prepare the functions for batch immunoassays. important application areas are bioanalysis and drug discovery.

  • 15.
    Marko-Varga, György
    et al.
    Department of Analytical Chemistry, Lund University, Lund, Sweden.
    Burestedt, Elisabeth
    Department of Analytical Chemistry, Lund University, Lund, Sweden.
    Svensson, Carl Johan
    Department of Analytical Chemistry, Lund University, Lund, Sweden.
    Emnéus, Jenny
    Department of Analytical Chemistry, Lund University, Lund, Sweden.
    Gorton, Lo
    Department of Analytical Chemistry, Lund University, Lund, Sweden.
    Ruzgas, Tautgirdas
    Enzyme Chemistry Laboratory, Institute of Biochemistry, Vilnius, Lithuania.
    Lutz, Mareike
    Division of Analytical Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands.
    Unger, Klaus K.
    Institute für Anorganische Chemie und Analytische Chemie, Johannes Gutenberg-Universität, Mainz, Germany.
    Effect of HY-Zeolites on the Performance of Tyrosinase-Modified Carbon Paste Electrodes1996Inngår i: Electroanalysis, ISSN 1040-0397, E-ISSN 1521-4109, Vol. 8, nr 12, s. 1121-1126Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The dependence of electrode response on additive properties in enzyme-modified carbon paste was studied. Four different HY-zeolite powders, dealuminated to different extents and characterized by both Si/Al ratio and hydrophilicity, were used as the carbon paste modifiers. The enzyme tyrosinase used in biosensors for the detection of catechol and other phenolic compounds was chosen as the model system for the construction of a composite carbon paste biosensor incorporating different HY-zeolites as additives. Tyrosinase was trapped on the HY-zeolite particles from a buffer solution, dried and mixed with graphite powder and a pasting oil. It was found that by incorporating HY-zeolites into the carbon paste the heterogeneous reaction rate of catechol redox conversion and the signal response for catechol were increased. In the latter case a higher response was observed for increased hydrophilicity, i.e., decreased Si/Al ratio of the HY-zeolite. The carbon paste/solution interface is considered to be an aqueous/organic phase and the characteristics of the enzyme-modified carbon paste electrode are related to theories, explaining enzymatic catalysis in organic solvents.

  • 16.
    Owens, Paul K.
    et al.
    Analytical Chemistry, Pharmaceutical R&D, Astra Hässle AB, Mölndal, Sweden.
    Karlsson, Lars
    Analytical Chemistry, Pharmaceutical R&D, Astra Hässle AB, Mölndal, Sweden.
    Lutz, Mareike
    Bioanalytical Chemistry, Astra Hässle AB, Mölndal, Sweden.
    Andersson, Lars I.
    Bioanalytical Chemistry, Concept Division, Astra Pain Control AB, Södertälje, Sweden.
    Molecular imprinting for bio- and pharmaceutical analysis1999Inngår i: TrAC. Trends in analytical chemistry, ISSN 0165-9936, E-ISSN 1879-3142, Vol. 18, nr 3, s. 146-154Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The potential of analytical techniques based on molecular imprinting is reviewed from the viewpoint of bio- and pharmaceutical analysis. A literature study shows that molecularly imprinted polymers (MIPs) have been implemented predominantly in three areas of interest to pharmaceutical industry laboratories. First, in sample preparation, imprinted polymers are used as the sorbent for solid phase extraction purposes. Secondly, MIPs serve as the stationary phase for analytical chromatographic and electrophoretic separations. Thirdly, imprinted polymers are utilised as analyte recognition materials in affinity assays. The advantages of MIPs, e.g., physical robustness, high strength, resistance to elevated temperatures and pressures, and inertness towards acids, bases, metal ions and organic solvents, have been well exploited in a large number of applications. This article focuses on how these benefits may be used for improving the quality of analytical procedures. Some key MIP disadvantages are also highlighted, especially in relation to other analytical techniques. (C) 1999 Published by Elsevier Science B.V. All rights reserved.

  • 17.
    Persson, Kajsa P.
    et al.
    DMPK & Bioanalytical Chemistry, AstraZeneca R&D Mölndal, Mölndal, Sweden & Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
    Ekehed, Susanne
    DMPK & Bioanalytical Chemistry, AstraZeneca R&D Mölndal, Mölndal, Sweden.
    Otter, Charlotta
    Molecular Pharmacology, AstraZeneca R&D Mölndal, Mölndal, Sweden.
    Lutz, E. S. Mareike
    DMPK & Bioanalytical Chemistry, AstraZeneca R&D Mölndal, Mölndal, Sweden.
    McPheat, Jane
    Molecular Pharmacology, AstraZeneca R&D Mölndal, Mölndal, Sweden.
    Masimirembwa, Collen M.
    DMPK & Bioanalytical Chemistry, AstraZeneca R&D Mölndal, Mölndal, Sweden & African Institute of Biomedical Science and Technology, Harare, Zimbabwe.
    Andersson, Tommy B.
    DMPK & Bioanalytical Chemistry, AstraZeneca R&D Mölndal, Mölndal, Sweden & Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Evaluation of Human Liver Slices and Reporter Gene Assays as Systems for Predicting the Cytochrome P450 Induction Potential of Drugs in Vivo in Humans2006Inngår i: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 23, nr 1, s. 56-69Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose

    The aim of the study was to investigate the feasibility of predicting human in vivo cytochrome P450 (CYP) induction properties of drugs using in vitro methods.

    Methods

    The CYP induction potential of compounds was tested in human liver slices and in reporter gene assays for the aryl hydrocarbon receptor (AhR) and the pregnane X receptor (PXR).

    Results

    In human liver slices, CYP activities decreased dramatically over the experimental period, whereas mRNA levels could reliably be used to investigate CYP1A, 2C9, and 3A4 induction. However, the interindividual variations and demanding experimentation limit the use of liver slices in screening programs. Reporter gene assays are robust and reliable assays, amenable to high throughput screening. Several compounds activated AhR. The relevance of this activation, however, needs to be further investigated since there are no clear reports on drugs inducing CYP1A in vivo. The results from the PXR assay could be used to correctly classify compounds with known CYP3A induction properties when relating in vivo AUCtot to PXR EC50 values.

    Conclusions

    Liver slices are a valuable model to study the regulation of a larger number of enzymes by single compounds. The PXR reporter gene assay could be used as a reliable screening method to predict CYP3A induction in vivo. © 2006 Springer Science + Business Media, Inc.

  • 18.
    Račaitytė, Kristina
    et al.
    Kaunas University of Technology, Department of Organic Technology, Kaunas, Lithuania.
    Lutz, Mareike
    Bioanalytical Chemistry, AstraZeneca R&D Mölndal, Mölndal, Sweden.
    Unger, Klaus K.
    Institut für Anorganische Chemie und Analytische Chemie, Johannes Gutenberg Universität, Mainz, Germany.
    Lubda, Dieter
    Merck KGaA, Specialty Laboratory Products, Darmstadt, Germany.
    Boos, Karl Siegfried
    Klinikum Grosshadern, Institut für Klinische Chemie, Munich, Germany.
    Analysis of neuropeptide Y and its metabolites by high-performance liquid chromatography–electrospray ionization mass spectrometry and integrated sample clean-up with a novel restricted-access sulphonic acid cation exchanger2000Inngår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 890, nr 1, s. 135-144Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A novel restricted access cation exchanger with sulphonic acid groups at the internal surface was proven to be highly suitable in the sample clean up of peptides on-line coupled to HPLC–electrospray ionization (ESI)-MS. Neuropeptide Y (NPY) and several of its fragments in plasma were subjected to the sample clean-up procedure. The peptides were eluted by a step gradient from the restricted access column, applying 10 mM phosphate buffer pH 3.5 from 5 to 20% (v/v) of acetonitrile with 1 M NaCl and transferred to a Micra ODS II column (33×4.6 mm). The separation of the peptides and their fragments was performed by a linear gradient from 20 to 60% (v/v) acetonitrile in water with 0.1% formic acid and 0.01% trifluoroacetic acid in 4 min at a flow-rate of 0.75 ml/min. An integrated and completely automated system composed of sample clean up–HPLC–ESI-MS was used to analyze real life samples. The sample volumes ranged between 20 and 100 μl. Peaks due to the fragments NPY 1–36, 3–36 and 13–36 in porcine plasma were identified by ESI-MS. The limit of detection was in the 5 nmol/ml range. The total analysis required 21 min and allowed the direct injection of plasma. © 2000 Elsevier Science B.V. All rights

  • 19.
    Rögnvaldsson, Thorsteinn
    et al.
    Högskolan i Halmstad, Akademin för informationsteknologi, Halmstad Embedded and Intelligent Systems Research (EIS).
    Brink, Joachim
    Högskolan i Halmstad.
    Florén, Henrik
    Högskolan i Halmstad, Akademin för ekonomi, teknik och naturvetenskap, Centrum för innovations-, entreprenörskaps- och lärandeforskning (CIEL).
    Gaspes, Veronica
    Högskolan i Halmstad, Akademin för informationsteknologi, Halmstad Embedded and Intelligent Systems Research (EIS).
    Holmgren, Noél
    University of Skövde, Skövde, Sweden.
    Lutz, Mareike
    Högskolan i Halmstad.
    Nilsson, Pernilla
    Högskolan i Halmstad, Akademin för lärande, humaniora och samhälle, Forskning om utbildning och lärande inom lärarutbildningen (FULL).
    Olsfelt, Jonas
    Högskolan i Halmstad.
    Svensson, Bertil
    Högskolan i Halmstad, Akademin för informationsteknologi, Halmstad Embedded and Intelligent Systems Research (EIS).
    Ericsson, Claes
    Högskolan i Halmstad, Akademin för lärande, humaniora och samhälle, Forskning om utbildning och lärande inom lärarutbildningen (FULL).
    Gustafsson, Linnea
    Högskolan i Halmstad, Akademin för lärande, humaniora och samhälle, Kontext & kulturgränser (KK).
    Hoveskog, Maya
    Högskolan i Halmstad, Akademin för ekonomi, teknik och naturvetenskap, Centrum för innovations-, entreprenörskaps- och lärandeforskning (CIEL).
    Hylander, Jonny
    Högskolan i Halmstad, Akademin för ekonomi, teknik och naturvetenskap, Bio- och miljösystemforskning (BLESS).
    Jonsson, Magnus
    Högskolan i Halmstad, Akademin för informationsteknologi, Halmstad Embedded and Intelligent Systems Research (EIS).
    Nygren, Jens
    Högskolan i Halmstad, Akademin för hälsa och välfärd, Centrum för forskning om välfärd, hälsa och idrott (CVHI).
    Rosén, Bengt-Göran
    Högskolan i Halmstad, Akademin för ekonomi, teknik och naturvetenskap, Maskinteknisk produktframtagning (MTEK).
    Sandberg, Mikael
    Högskolan i Halmstad, Akademin för lärande, humaniora och samhälle, Centrum för samhällsanalys (CESAM).
    Benner, Mats
    Lund University, Lund, Sweden.
    Berg, Martin
    Högskolan i Halmstad, Akademin för lärande, humaniora och samhälle, Centrum för samhällsanalys (CESAM).
    Bergvall, Patrik
    Högskolan i Halmstad.
    Carlborg, Anna
    Högskolan i Halmstad.
    Fleischer, Siegfried
    Högskolan i Halmstad, Akademin för ekonomi, teknik och naturvetenskap, Bio- och miljösystemforskning (BLESS).
    Hållander, Magnus
    Högskolan i Halmstad, Akademin för informationsteknologi, Halmstad Embedded and Intelligent Systems Research (EIS).
    Mattsson, Marie
    Högskolan i Halmstad, Akademin för ekonomi, teknik och naturvetenskap, Bio- och miljösystemforskning (BLESS).
    Olsson, Charlotte
    Högskolan i Halmstad, Akademin för ekonomi, teknik och naturvetenskap, Bio- och miljösystemforskning (BLESS).
    Pettersson, Håkan
    Högskolan i Halmstad, Akademin för informationsteknologi, Halmstad Embedded and Intelligent Systems Research (EIS).
    Rundquist, Jonas
    Högskolan i Halmstad, Akademin för ekonomi, teknik och naturvetenskap, Centrum för innovations-, entreprenörskaps- och lärandeforskning (CIEL).
    Sahlén, Göran
    Högskolan i Halmstad, Akademin för ekonomi, teknik och naturvetenskap, Bio- och miljösystemforskning (BLESS).
    Waara, Sylvia
    Högskolan i Halmstad, Akademin för ekonomi, teknik och naturvetenskap, Bio- och miljösystemforskning (BLESS).
    Weisner, Stefan
    Högskolan i Halmstad, Akademin för ekonomi, teknik och naturvetenskap, Bio- och miljösystemforskning (BLESS).
    Werner, Sven
    Högskolan i Halmstad, Akademin för ekonomi, teknik och naturvetenskap, Bio- och miljösystemforskning (BLESS).
    ARC13 – Assessment of Research and Coproduction: Reports from the assessment of all research at Halmstad University 20132014Rapport (Annet (populærvitenskap, debatt, mm))
    Abstract [en]

    During 2013, an evaluation of all the research conducted at Halmstad University was carried out. The purpose was to assess the quality of the research, coproduction, and collaboration in research, as well as the impact of the research. The evaluation was dubbed the Assessment of Research and Coproduction 2013, or ARC13. (Extract from Executive Summary)

  • 20.
    Sjöberg, Åsa
    et al.
    Global In Silico & In Vitro DMPK, AstraZeneca R&D, Mölndal, Sweden.
    Lutz, Mareike
    CVGI iMED DMPK AstraZeneca R&D, Mölndal, Sweden.
    Tannergren, Christer
    Medicines Evaluation, Pharmaceutical Development, AstraZeneca R&D, Mölndal, Sweden.
    Wingolf, Caroline
    Medicines Evaluation, Pharmaceutical Development, AstraZeneca R&D, Mölndal, Sweden.
    Borde, Anders
    Medicines Evaluation, Pharmaceutical Development, AstraZeneca R&D, Mölndal, Sweden.
    Ungell, Anna-Lena
    CVGI iMED DMPK AstraZeneca R&D, Mölndal, Sweden.
    Comprehensive study on regional human intestinal permeability and prediction of fraction absorbed of drugs using the Ussing chamber technique2013Inngår i: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 48, nr 1-2, s. 166-180Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The purpose of this study was to evaluate the use of human intestinal tissue in Ussing chamber to predict oral and colonic drug absorption and intestinal metabolism. Data on viability, correlation between apparent permeability coefficients (Papp) and fraction absorbed (fa) after oral and colonic administration, regional permeability, active uptake and efflux of drugs as well as intestinal metabolism were compiled from experiments using 159 human donors. Permeability coefficients for up to 28 drugs were determined using one or several of four intestinal regions: duodenum, jejunum, ileum and colon and 10 drugs were studied bidirectionally. Viability was monitored simultaneously with transport experiments by recording potential difference (PD), short-circuit current (SCC) and the resistance (TER). Intestinal metabolism was studied using testosterone and midazolam as probe substrates.

    There was a steep sigmoidal correlation between Papp in the Ussing chamber, using jejunal segments, and oral fa in humans, for a set of 25 drugs (R2: 0.85, p < 0.01). A clear sigmoidal relationship was also obtained between Papp in colonic segments and fa after colonic administration in humans for a set of 10 drugs (R2: 0.93, p < 0.05). Regional permeability data showed a tendency for highly permeable compounds to have higher or similar Papp in colon as in the small intestinal segments, while the colonic regions showed a lower Papp for more polar compounds as well as for d-glucose and l-leucine. Bidirectional transport (mucosa to serosa and serosa to mucosa direction) in jejunum showed well functioning efflux- and uptake asymmetry. Intestinal metabolic extraction during transport across jejunum segments was found for both testosterone and midazolam.

    In conclusion, viable excised human intestine mounted in the Ussing chamber, is a powerful technique for predicting regional fraction absorbed (fa), transporter-mediated uptake or efflux as well as intestinal metabolism of drug candidates in man. Furthermore, a sigmoidal relationship of Papp vs. fa was obtained when permeability data from the present study were merged with data from 2 other independent laboratories (R2: 0.83, p < 0.01). The correlation curve reported can be used by any laboratory for predictions of human permeability and fa. In addition, for the first time a correlation curve between colonic Papp and human colonic fa is reported, which demonstrates the usefulness of this methodology in early assessment of the colonic absorption potential of extended release formulation candidates. © 2012 Elsevier B.V. All rights reserved.

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