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Lutz, Mareike
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Rögnvaldsson, T., Brink, J., Florén, H., Gaspes, V., Holmgren, N., Lutz, M., . . . Sandberg, M. (2014). ARC13 – Assessment of Research and Coproduction: Reports from the assessment of all research at Halmstad University 2013. Halmstad: Halmstad University Press
Open this publication in new window or tab >>ARC13 – Assessment of Research and Coproduction: Reports from the assessment of all research at Halmstad University 2013
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2014 (English)Report (Other (popular science, discussion, etc.))
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)

Place, publisher, year, edition, pages
Halmstad: Halmstad University Press, 2014. p. 110
Keywords
Halmstad University, research evaluation, coproduction
National Category
Other Social Sciences not elsewhere specified
Identifiers
urn:nbn:se:hh:diva-24789 (URN)978-91-87045-06-6 (ISBN)978-91-87045-05-9 (ISBN)
Funder
Knowledge Foundation
Available from: 2014-03-10 Created: 2014-03-05 Last updated: 2019-04-17Bibliographically approved
Desbans, C., Hilgendorf, C., Lutz, M., Bachellier, P., Zacharias, T., Weber, J., . . . Ungell, A.-L. (2014). Prediction of fraction metabolized via CYP3A in humans utilizing cryopreserved human hepatocytes from a set of 12 single donors. Xenobiotica, 44(1), 17-27
Open this publication in new window or tab >>Prediction of fraction metabolized via CYP3A in humans utilizing cryopreserved human hepatocytes from a set of 12 single donors
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2014 (English)In: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 44, no 1, p. 17-27Article in journal (Refereed) Published
Place, publisher, year, edition, pages
London, United Kingdom: Informa Healthcare, 2014
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:hh:diva-27126 (URN)10.3109/00498254.2013.809617 (DOI)000328261300003 ()23883428 (PubMedID)2-s2.0-84890512792 (Scopus ID)
Available from: 2014-11-26 Created: 2014-11-26 Last updated: 2018-03-22Bibliographically approved
Johannesson, P., Bratt, E., Broo, A., Evertsson, E., Judkins, R., Leandersson, C., . . . Lindstedt, E.-L. (2014). SAR and optimization of trioxoisothiazole-based liver receptor X (LXR) agonists leading to the clinical candidate AZD3971. In: Division of Medicinal Chemistry: Scientific Abstracts for the 248th National Meeting and Exposition: August 10-14, 2014: San Francisco, CA. Paper presented at 248th ACS (American Chemical Society) National Meeting, San Francisco, CA, USA, August 10-14, 2014 (pp. 247-247). , 248
Open this publication in new window or tab >>SAR and optimization of trioxoisothiazole-based liver receptor X (LXR) agonists leading to the clinical candidate AZD3971
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2014 (English)In: Division of Medicinal Chemistry: Scientific Abstracts for the 248th National Meeting and Exposition: August 10-14, 2014: San Francisco, CA, 2014, Vol. 248, p. 247-247Conference paper, Oral presentation with published abstract (Refereed)
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.

National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:hh:diva-26706 (URN)000349167402150 ()
Conference
248th ACS (American Chemical Society) National Meeting, San Francisco, CA, USA, August 10-14, 2014
Available from: 2014-10-10 Created: 2014-10-10 Last updated: 2018-03-22Bibliographically approved
Sjöberg, Å., Lutz, M., Tannergren, C., Wingolf, C., Borde, A. & Ungell, A.-L. (2013). Comprehensive study on regional human intestinal permeability and prediction of fraction absorbed of drugs using the Ussing chamber technique. European Journal of Pharmaceutical Sciences, 48(1-2), 166-180
Open this publication in new window or tab >>Comprehensive study on regional human intestinal permeability and prediction of fraction absorbed of drugs using the Ussing chamber technique
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2013 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 48, no 1-2, p. 166-180Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Amsterdam: Elsevier B.V, 2013
Keywords
Ussing chamber, Human intestine, Absorption, Intestinal permeability, Regional permeability, Intestinal metabolism
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:hh:diva-24117 (URN)10.1016/j.ejps.2012.10.007 (DOI)000315613500019 ()23103351 (PubMedID)2-s2.0-84870163047 (Scopus ID)
Available from: 2013-12-16 Created: 2013-12-09 Last updated: 2018-03-22Bibliographically approved
Andersson, P., Kenne, K., Glinghammar, B., Pointon, A. V., Åkerblad, P., Lutz, M., . . . Lindstedt, E.-L. (2012). Toxicity with LXR agonists – Problem solving activities for mechanistic understanding. Paper presented at EUROTOX 2012, 48th Congress of the European Societies of Toxicology, Stockholm, Sweden, 17-20 June, 2012. Toxicology Letters, 211(Suppl. (S)), S39-S39
Open this publication in new window or tab >>Toxicity with LXR agonists – Problem solving activities for mechanistic understanding
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2012 (English)In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, no Suppl. (S), p. S39-S39Article in journal, Meeting abstract (Refereed) Published
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.

Place, publisher, year, edition, pages
Shannon: Elsevier, 2012
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:hh:diva-28241 (URN)10.1016/j.toxlet.2012.03.163 (DOI)000305173900125 ()
Conference
EUROTOX 2012, 48th Congress of the European Societies of Toxicology, Stockholm, Sweden, 17-20 June, 2012
Available from: 2015-05-11 Created: 2015-05-11 Last updated: 2018-03-22Bibliographically approved
Desbans, C., Hilgendorf, C., Richert, L., Lutz, M. & Ungell, A.-L. (2010). Accurate prediction of variability in CLint and Fm via 3A4 is only obtained by assessing a series of individual cryopreserved human hepatocyte batches. Paper presented at 9th International Meeting of the International Society for the Study of Xenobiotics (ISSX), Istanbul, Turkey, September 4-8, 2010. Drug metabolism reviews (Softcover ed.), 42(Suppl. 1), 274-274
Open this publication in new window or tab >>Accurate prediction of variability in CLint and Fm via 3A4 is only obtained by assessing a series of individual cryopreserved human hepatocyte batches
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2010 (English)In: Drug metabolism reviews (Softcover ed.), ISSN 0360-2532, E-ISSN 1097-9883, Vol. 42, no Suppl. 1, p. 274-274Article in journal, Meeting abstract (Refereed) Published
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’

Place, publisher, year, edition, pages
New York: Informa Healthcare, 2010
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:hh:diva-24118 (URN)000281147700486 ()
Conference
9th International Meeting of the International Society for the Study of Xenobiotics (ISSX), Istanbul, Turkey, September 4-8, 2010
Available from: 2013-12-16 Created: 2013-12-09 Last updated: 2018-03-22Bibliographically approved
Persson, K. P., Ekehed, S., Otter, C., Lutz, E. S., McPheat, J., Masimirembwa, C. M. & Andersson, T. B. (2006). Evaluation of Human Liver Slices and Reporter Gene Assays as Systems for Predicting the Cytochrome P450 Induction Potential of Drugs in Vivo in Humans. Pharmaceutical research, 23(1), 56-69
Open this publication in new window or tab >>Evaluation of Human Liver Slices and Reporter Gene Assays as Systems for Predicting the Cytochrome P450 Induction Potential of Drugs in Vivo in Humans
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2006 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 23, no 1, p. 56-69Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
New York: Springer, 2006
Keywords
AhR, CYP induction, human liver slices, in vitro–in vivo correlation, PXR, reporter gene assay
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:hh:diva-24119 (URN)10.1007/s11095-005-8812-5 (DOI)000235135400005 ()16328606 (PubMedID)2-s2.0-32244447844 (Scopus ID)
Available from: 2013-12-16 Created: 2013-12-09 Last updated: 2018-03-22Bibliographically approved
Lutz, M., Markling, M. E. & Masimirembwa, C. M. (2002). Monolithic silica rod liquid chromatography with ultraviolet or fluorescence detection for metabolite analysis of cytochrome P450 marker reactions. Journal of chromatography. B, 780(2), 205-215
Open this publication in new window or tab >>Monolithic silica rod liquid chromatography with ultraviolet or fluorescence detection for metabolite analysis of cytochrome P450 marker reactions
2002 (English)In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 780, no 2, p. 205-215Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Amsterdam: Elsevier, 2002
Keywords
Monolithic silica rod, Cytochrome P450
National Category
Analytical Chemistry
Identifiers
urn:nbn:se:hh:diva-24120 (URN)10.1016/S1570-0232(02)00264-7 (DOI)000179132000001 ()12401345 (PubMedID)2-s2.0-0037175432 (Scopus ID)
Available from: 2013-12-16 Created: 2013-12-09 Last updated: 2018-03-22Bibliographically approved
Račaitytė, K., Lutz, M., Unger, K. K., Lubda, D. & Boos, K. S. (2000). 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 exchanger. Journal of Chromatography A, 890(1), 135-144
Open this publication in new window or tab >>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 exchanger
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2000 (English)In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 890, no 1, p. 135-144Article in journal (Refereed) Published
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

Place, publisher, year, edition, pages
Amsterdam: Elsevier B.V, 2000
Keywords
Restricted-access media, Sample handling, Column switching, Neuropeptides, Peptides
National Category
Analytical Chemistry
Identifiers
urn:nbn:se:hh:diva-24121 (URN)10.1016/S0021-9673(00)00639-7 (DOI)000088736900014 ()10976801 (PubMedID)2-s2.0-0343962626 (Scopus ID)
Available from: 2013-12-16 Created: 2013-12-09 Last updated: 2018-03-22Bibliographically approved
Larsson, M. & Lutz, M. (2000). Transient isotachophoresis for sensitivity enhancement in capillary electrophoresis-mass spectrometry for peptide analysis. Electrophoresis, 21(14), 2859-2865
Open this publication in new window or tab >>Transient isotachophoresis for sensitivity enhancement in capillary electrophoresis-mass spectrometry for peptide analysis
2000 (English)In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 21, no 14, p. 2859-2865Article in journal (Refereed) Published
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).

Place, publisher, year, edition, pages
Weinheim: Wiley-VCH Verlagsgesellschaft, 2000
Keywords
Isotachophoresis, Capillary electrophoresis, Mass spectrometry, Peptides
National Category
Analytical Chemistry
Identifiers
urn:nbn:se:hh:diva-24122 (URN)10.1002/1522-2683(20000801)21:14<2859::AID-ELPS2859>3.0.CO;2-F (DOI)000089275400015 ()11001295 (PubMedID)2-s2.0-0033821046 (Scopus ID)
Available from: 2013-12-16 Created: 2013-12-09 Last updated: 2018-03-22Bibliographically approved

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