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  • 101.
    Hellqvist, Alexander
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Heiene, Reidun
    Hedeland, Ylva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    A robust and reliable capillary electrophoretic method for quantitative determination of iohexol in plasma2012Conference paper (Refereed)
  • 102.
    Henrohn, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Sandqvist, Anna
    Umeå universitet.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Egeröd, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Wikström, Gerhard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Acute haemodynamic response in relation to plasma vardenafil concentrations in patients with pulmonary hypertension2012In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 74, no 6, p. 990-998Article in journal (Refereed)
    Abstract [en]

    AIMS

    To evaluate the acute haemodynamic effects of a single oral dose of vardenafil and to study the drug concentration in relation to haemodynamic effects in patients with pulmonary hypertension (PH).

    METHODS

    Sixteen patients with PH (aged 29–85\ years), received one single oral dose of vardenafil (5, 10 or 20 mg). The haemodynamic effect was assessed over a 60 min period. Vardenafil plasma concentrations were measured after 15, 30, 45 and 60 min using liquid chromatography–tandem mass spectrometry.

    RESULTS

    At 60 min a reduction in mPAP with a median % decrease of −20.3% (range −48.3 to 3.0; P < 0.001) and an increase in cardiac output and the cardiac index with a median % change of 10.6% (range −25.0 to 88.1; P = 0.015) and 12.1% (range −24.0 to 94.4; P = 0.01) respectively was observed. The pulmonary vascular resistance (PVR) was reduced with a median % decrease of −28.9% (range −61.5 to −5.9; P < 0.001), and pulmonary selectivity was reflected by a median percent reduction of −16.9% (range −49.0 to 16.5; P = 0.002; n = 14) in the PVR/systemic vascular resistance ratio. There was a correlation between the plasma concentrations of vardenafil and change in mPAP (r = −0.579, P = 0.019) and between vardenafil concentrations and change in PVR (r = −0.662, P = 0.005).

    CONCLUSIONS

    Vardenafil causes rapid changes in cardiopulmonary haemodynamics and there is a correlation between plasma vardenafil drug concentration and the acute changes in mPAP as well as PVR in patients with PH.

  • 103.
    Häggblad Sahlberg, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Mortensen, Anja C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Haglöf, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Engskog, Mikael K. R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Arvidsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Nestor, Marika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Different functions of AKT1 and AKT2 in molecular pathways, cell migration and metabolism in colon cancer cells2017In: International Journal of Oncology, ISSN 1019-6439, Vol. 50, no 1, p. 5-14Article in journal (Refereed)
    Abstract [en]

    AKT is a central protein in many cellular pathways such as cell survival, proliferation, glucose uptake, metabolism, angiogenesis, as well as radiation and drug response. The three isoforms of AKT (AKT1, AKT2 and AKT3) are proposed to have different physiological functions, properties and expression patterns in a cell type-dependent manner. As of yet, not much is known about the influence of the different AKT isoforms in the genome and their effects in the metabolism of colorectal cancer cells. In the present study, DLD-1 isogenic AKT1, AKT2 and AKT'/2 knockout colon cancer cell lines were used as a model system in conjunction with the parental cell line in order to further elucidate the differences between the AKT isoforms and how they are involved in various cellular pathways. This was done using genome wide expression analyses, metabolic profiling and cell migration assays. In conclusion, downregulation of genes in the cell adhesion, extracellular matrix and Notch-pathways and upregulation of apoptosis and metastasis inhibitory genes in the p53-pathway, confirm that the knockout of both AKT1 and AKT2 will attenuate metastasis and tumor cell growth. This was verified with a reduction in migration rate in the AKT1 KO and AKT2 KO and most explicitly in the AKT1/2 KO. Furthermore, the knockout of AKT1, AKT2 or both, resulted in a reduction in lactate and alanine, suggesting that the metabolism of carbohydrates and glutathione was impaired. This was further verified in gene expression analyses, showing downregulation of genes involved in glucose metabolism. Additionally, both AKT1 KO and AKT2 KO demonstrated an impaired fatty acid metabolism. However, genes were upregulated in the Wnt and cell proliferation pathways, which could oppose this effect. AKT inhibition should therefore be combined with other effectors to attain the best effect.

  • 104. Ingvast-Larsson, C.
    et al.
    Högberg, M.
    Mengistu, U.
    Olsén, L.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Olsson, K.
    Pharmacokinetics of meloxicam in adult goats and its analgesic effect in disbudded kids2011In: Journal of Veterinary Pharmacology and Therapeutics, ISSN 0140-7783, E-ISSN 1365-2885, Vol. 34, no 1, p. 64-69Article in journal (Refereed)
    Abstract [en]

    The pharmacokinetics and analgesic effect of the nonsteroidal anti-inflammatory drug meloxicam (0.5 mg/kg) in goats were investigated. In a randomized, cross-over design the pharmacokinetic parameters were investigated in adult goats (n = 8) after single intravenous and oral administration. The analgesic effect was evaluated in kids using a randomized, placebo controlled and blinded protocol. Kids received meloxicam (n = 6) once daily and their siblings (n = 5) got isotonic NaCl intramuscularly while still anaesthetized after cautery disbudding and injections were repeated on three consecutive days. In the adult goats after intravenous administration the terminal half-life was 10.9 ± 1.7 h, steady-state volume of distribution was 0.245 ± 0.06 L/kg, and total body clearance was 17.9 ± 4.3 mL/h/kg. After oral administration bioavailability was 79 ± 19%, C(max) was 736 ± 184 ng/mL, T(max) was 15 ±5 h, although the terminal half-life was similar to the intravenous value, 11.8 ± 1.7 h. Signs of pain using a visual analogue scale were smaller in kids treated with meloxicam compared with kids treated with placebo on the first day after disbudding, but subsequently no difference in pain was noticeable. Plasma cortisol and glucose concentrations did not differ between the two groups.

  • 105. Ingvast-Larsson, Carina
    et al.
    Holgersson, Anja
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Lagerstedt, Anne-Sofie
    Olsson, Kerstin
    Clinical pharmacology of methadone in dogs2010In: Veterinary Anaesthesia and Analgesia, ISSN 1467-2987, E-ISSN 1467-2995, Vol. 37, no 1, p. 48-56Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate the pharmacokinetics and effects of methadone on behaviour and plasma concentrations of cortisol and vasopressin in healthy dogs. Study design Randomized, cross-over, experimental trial. Animals Nine adult dogs (beagle and beagle cross breeds), four males and five females. Methods Methadone hydrochloride, 0.4 mg kg-1, was administered intravenously (IV) and subcutaneously (SC) with a crossover design. Drug and hormone analyses in plasma were performed using Liquid Chromatography-Electrospray Ionization-Tandem Mass Spectrometry and radioimmunoassay respectively. Behavioural data were collected using a standardized protocol. Results After IV administration, the plasma concentration of methadone at 10 minutes was 82.1 +/- 9.2 ng mL-1 (mean +/- SD), the terminal half-life was 3.9 +/- 1.0 hours, the volume of distribution 9.2 +/- 3.3 L kg-1 and plasma clearance 27.9 +/- 7.6 mL minute-1 kg-1. After SC administration, time to maximal plasma concentration was 1.26 +/- 1.04 hours and maximal plasma concentration of methadone was 23.9 +/- 14.4 ng mL-1, the terminal half-life was 10.7 +/- 4.3 hours and bioavailability was 79 +/- 22%. Concentrations of both cortisol and vasopressin were increased for an hour following IV methadone. The observed behavioural effects of methadone were decreased licking and swallowing and an increase in whining after SC administration. The latter finding is notable as it can be misinterpreted as pain when methadone is used as an analgesic. Conclusion and clinical relevance When methadone was administered by the SC route, the half-life was longer, but the individual variation in plasma concentrations was greater compared with IV administration. Increased frequency of whining occurred after administration of methadone and may be a drug effect and not a sign of pain. Cortisol and vasopressin concentrations in plasma may not be suitable for evaluating analgesia after methadone treatment.

  • 106.
    Jama, Fosia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Evaluation of amino acids in Aminoven 10 % and Vamin 18EF with UPLC using Waters AccQTag method2013Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The aim with this project was to evaluate Waters AccQTag method which was ananalytical method that Waters Corporation provides for determination of aminoacids. The amino acid analysis was carried out by reversed-phase AQUITY UPLCH-Class, using a BEH C18-column and a PDA detector.Both primary and secondary amino acids were analyzed after precolumnderivatization with the AccQTag reagent kit by a manual procedure and, detected at260 nm. Fresenius Kabis existing products, Aminoven 10 % and Vamin 18EF wereused as samples. The evaluation was based on external calibration curves withprepared standard solutions from Fresenius Kabi, with the addition of the internalstandard L-Norvaline. Waters amino acid standard was used for the system suitabilitytest. A validation according to the ICH guidelines were performed with the followingparameters: specificity, linearity, precision, LOQ, LOD and robustness.Complementary parameters for system suitability test (SST) and stability of standardand reagent were also evaluated. The validation showed that the % RSD values forspecificity, system suitability test and robustness were within the acceptance criteriaof equal or less than 3 % for amino acids. Although the precision were between1.3-7.5 % which was higher than the acceptance criteria of equal or less than 3 %, thiswas likely due to sensitive sample preparation. The linearity was bad which made itimpossible to quantify the method since the calibration curves were below 0.999. Itwas concluded that the system was robust and can be used to analyze amino acids inAminoven 10 % and Vamin 18EF but the preparation step should if possible beautomatized to achieve better precision in the analytical work. Two amino acids,cysteine and histidine, needs to be studied further; cysteine gave three peaks insteadof one and histidine gave a peak split at higher injection volume than 0.5 uL.

  • 107. Jarmalaviciene, Reda
    et al.
    Kornysova, Olga
    Bendokas, Vidmantas
    Westerlund, Douglas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Buszewski, Boguslaw
    Maruska, Audrius
    Restricted-access media development for direct analysis of drugs in biofluids using capillary liquid chromatography2008In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 391, no 6, p. 2323-2328Article in journal (Refereed)
    Abstract [en]

    In analytical sciences the design of novel materials and stationary phases for the sample preparation and separation of analytes from biological fluids is needed. In this work we present different strategies for modification of stationary phases to produce tailored solutions for the analytical problem. In this context a novel shielded polymeric reversed-phase monolithic material was prepared in the presence of different numbers of reactive groups and concentrations of the coating polymer. Chromatographic experiments were performed using benzoic acid propyl ester in order to characterize the hydrophobicity and efficiency of the different restricted-access continuous beds prepared. Inverse size-exclusion chromatography was used for investigation of the pore structure properties of the beds. Capillary columns were applied for nanochromatography of biological fluids containing a mixture of nitrazepamum and medazepamum.

  • 108.
    Johansson, Monika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Fransson, Dick
    Rundlöf, Torgny
    Huynh, Ngoc-Hang
    Arvidsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    A general analytical platform and strategy in search for illegal drugs2014In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 100, p. 215-229Article in journal (Refereed)
    Abstract [en]

    An effective screening procedure to identify and quantify active pharmaceutical substances in suspected illegal medicinal products is described. The analytical platform, consisting of accurate mass determination with liquid chromatography time-of-flight mass spectrometry (LC-QTOF-MS) in combination with nuclear magnetic resonance (NMR) spectroscopy provides an excellent analytical tool to screen for unknowns in medicinal products, food supplements and herbal formulations. This analytical approach has been successfully applied to analyze thousands of samples. The general screening method usually starts with a methanol extraction of tablets/capsules followed by liquid chromatographic separation on a Halo Phenyl-Hexyl column (2.7μm; 100mm×2.1mm) using an acetonitrile/0.1% formic acid gradient as eluent. The accurate mass of peaks of interest was recorded and a search made against an in-house database containing approximately 4200 substances, mostly pharmaceutical compounds. The search could be general or tailored against different classes of compounds. Hits were confirmed by analyzing a reference substance and/or by NMR. Quantification was normally performed with quantitative NMR (qNMR) spectroscopy. Applications for weight-loss substances like sibutramine and orlistat, sexual potency enhancement (PDE-5 inhibitors), and analgesic drugs are presented in this study. We have also identified prostaglandin analogues in eyelash growth serum, exemplified by isopropyl cloprostenate and bimatoprost. For creams and ointments, matrix solid-phase dispersion (MSPD) was found to give a clean extracts with high recovery prior to LC-MS analyses. The structural elucidation of cetilistat, a new weight-loss substance recently found in illegal medicines purchased over the Internet, is also presented.

  • 109.
    Karlsson, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Almgren, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Reversal of Enantiomeric Retention Order by Using a Single N-Derivatized Dipeptide as Chiral Mobile Phase Additive and Porous Graphitised Carbon as Stationary Phase2007In: Chromatographia, ISSN 0009-5893, E-ISSN 1612-1112, Vol. 66, no 5-6, p. 349-356Article in journal (Refereed)
    Abstract [en]

    In this work the three dipeptides, Z-l-alanyl-l-glutaric acid (Z-l-ala-l-glu), Z-l-phenylanyl-l-glutaric acid (Z-l-phe-l-glu) and Z-glycyl-l-glutaric acid (Z-gly-l-glu) were tested as chiral counter ions for enantiomeric resolution of amino alcohols. The influence of solute and counter ion structure upon retention and enantioselectivity was evaluated. The chiral counter ions were dissolved in a mixture of polar solvents, i.e., ethyl acetate, methanol and acetonitrile and the achiral solid phase used was porous graphitic carbon, marketed as Hypercarb. The enantioselectivities observed for the tested solutes were highly influenced by the used chiral counter ion structure. For example no enantioselectivity was observed for (R,S)-alprenolol using Z-l-ala-l-glu while a separation factor (α) of 1.59 was obtained using Z-l-phe-l-glu as chiral counter ion. High selectivity factors (α > 2.7) were observed between enantiomers of tertiary amines using Z-l-phe-l-glu as counter ion. Interestingly, the structure of the counter ion, as well as the charge on Z-l-phe-l-glu and the mobile phase solvent composition, influenced the retention order of the enantiomers.

  • 110.
    Kjellberg, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Evaluation of a UPLC-MS method using 18O-labelled water for the identification of hydrolytic degradants of drug substances2015Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    In this master’s thesis the hydrolytic degradation in 18O-water solutions of six drug substances has been studied. The aim was to develop a mass spectrometric method for easier identification of degradants, since hydrolysis in 18O-water will generate degradants with higher mass compared with hydrolysis in regular water.

    The degradation was carried out in both acidic and basic conditions. About 10 % degradation was aimed for in the study and the storage time and conditions were adjusted to accommodate that. The samples were then analyzed with UPLC-MS. Separation was achieved on either an Acquity BEH C18 or HSS T3, 100 x 2.1 mm, 1.7 μm column. The mobile phases consisted of water and acetonitrile with the addition of 0.1 % formic acid.

    Structures for the detected degradants were proposed based on the molecular ion data from the regular and 18O-experiments. Most of these degradants have previously been reported. Structures for some previously unreported degradants are also proposed. These structures should need to be confirmed with future studies.

    The usefulness of the 18O-method has been evaluated and it was concluded that it is valuable to use as a complement to the generic hydrolytic experiment. In this study, the extra information gained from the 18O-experiment was used to confirm a number of proposed structures. It was also crucial in the rejection of two proposed structures for degradants of duloxetine. The method is most useful when confirming water involvement in reactions, for example in drug degradation. It is also a good alternative for obtaining structural information if the laboratory does not own a high-resolution MS.

  • 111.
    Knych, Heather K.
    et al.
    Univ Calif Davis, Sch Vet Med, KL Maddy Equine Analyt Chem Lab, 620 West Hlth Sci Dr, Davis, CA 95616 USA.;Univ Calif Davis, Sch Vet Med, Dept Vet Mol Biosci, 620 West Hlth Sci Dr, Davis, CA 95616 USA..
    Stanley, Scott D.
    Univ Calif Davis, Sch Vet Med, KL Maddy Equine Analyt Chem Lab, 620 West Hlth Sci Dr, Davis, CA 95616 USA.;Univ Calif Davis, Sch Vet Med, Dept Vet Mol Biosci, 620 West Hlth Sci Dr, Davis, CA 95616 USA..
    McKemie, Dan S.
    Univ Calif Davis, Sch Vet Med, KL Maddy Equine Analyt Chem Lab, 620 West Hlth Sci Dr, Davis, CA 95616 USA..
    Arthur, Rick M.
    Univ Calif Davis, Sch Vet Med, 620 West Hlth Sci Dr, Davis, CA 95616 USA..
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry. Natl Vet Inst SVA, Uppsala, Sweden..
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry. Natl Vet Inst SVA, Uppsala, Sweden..
    Thevis, Mario
    German Sport Univ Cologne, Ctr Prevent Doping Res, Inst Biochem, Cologne, Germany..
    Kass, Philip H.
    Univ Calif Davis, Sch Vet Med, Dept Populat Hlth & Reprod, 620 West Hlth Sci Dr, Davis, CA 95616 USA..
    Pharmacokinetics and pharmacodynamics of meldonium in exercised thoroughbred horses2017In: Drug Testing and Analysis, ISSN 1942-7603, E-ISSN 1942-7611, Vol. 9, no 9, p. 1392-1399Article in journal (Refereed)
    Abstract [en]

    Although developed as a therapeutic medication, meldonium has found widespread use in human sports and was recently added to the World Anti-Doping Agency's list of prohibited substances. Its reported abuse potential in human sports has led to concern by regulatory authorities about the possible misuse of meldonium in equine athletics. The potential abuse in equine athletes along with the limited data available regarding the pharmacokinetics and pharmacodynamics of meldonium in horses necessitates further study. Eight exercised adult thoroughbred horses received a single oral dose of 3.5, 7.1, 14.3 or 21.4 mg/kg of meldonium. Blood and urine samples were collected and analyzed using liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were determined using non-compartmental analysis. Maximum serum concentrations ranged from 440.2 to 1147 ng/mL and the elimination half-life from 422 to 647.8 h. Serum concentrations were below the limit of quantitation by days 4, 7, 12 and 12 for doses of 3.5, 7.1, 14.3 and 21.4 mg/kg, respectively. Urine concentrations were below the limit of detection by day 44 following administration of 3.5 mg/kg and day 51 for all other dose groups. No adverse effects were observed following meldonium administration. While the group numbers were small, changes in heart rate were observed in the 3.5 mg/kg dose group (n = 1). Glucose concentrations changed significantly in all dose groups studied (n = 2 per dose group). Similar to that reported for humans, the detection time of meldonium in biological samples collected from horses is prolonged, which should allow for satisfactory regulation in performance horses. Copyright (C) 2017 John Wiley & Sons, Ltd.

  • 112. Krug, Oliver
    et al.
    Thomas, Andreas
    Beuck, Simon
    Schenk, Ina
    Machnik, Marc
    Schänzer, Wilhelm
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Thevis, Mario
    Characterization of In Vitro Synthesized Equine Metabolites of the Selective Androgen Receptor Modulators S24 and S42012In: Journal of Equine Veterinary Science, ISSN 0737-0806, E-ISSN 1542-7412, Vol. 32, no 9, p. 562-568Article in journal (Refereed)
    Abstract [en]

    Several selective androgen receptor modulators (SARMs) have been synthesized and investigated in humans, rats, and dogs in the past, but no data are yet available concerning the metabolism of SARMs in horses. The aryl-propionamide-derived drug candidates S24 and S4 (andarine) have a strong androgen receptor binding affinity and show distinctive specific cell answers. Although no SARM drug candidate (aiming for testosterone replacement therapy) has completed clinical trials yet, S4 has been illicitly available via the Internet. These facts led to the prohibition of SARMs by the German equestrian federation, and the (mis)use of such compounds would further represent a doping rule violation in horse racing. In this study, the drug candidates S24 and S4 were subjected to in vitro metabolism experiments with equine liver microsomal preparations from a female Quarter Horse to obtain information about potential target analytes in equine doping control analysis. The enzymatically synthesized metabolites were characterized by liquid chromatography–tandem mass spectrometry and –high-resolution/high-accuracy mass spectrometry. All observed S24 and S4 equine metabolites are in agreement with earlier in vitro and in vivo studies in humans and dogs. Nevertheless, the relative percentage of generated equine metabolites (as determined from the analytes’ response in full-scan chromatography–tandem mass spectrometry and –high-resolution/high-accuracy mass spectrometry measurements) differs considerably from the reported profiles. Although the S24 metabolite pattern is comparably balanced concerning glucuronidated and sulfonated conjugates, the major S4 metabolite was found to be the unconjugated dephenylated compound, with a proportion of more than 90%.

  • 113.
    Kölfeldt, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Development and evaluation of sample preparation procedure for human plasma samples in LC/MS-based metabolomics2015Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The aim of this master thesis project was to develop methods for sample preparation and analysis by LC-MS suitable for global metabolomics of human plasma samples. In this thesis six different methods was tested, based on precipitation, solid phase extraction (SPE), and ultrafiltration. The methods differ in their mechanisms of action, but the end goal is the same, to remove the proteins and other high molecular weight compounds from the samples and to retain as many metabolites as possible in a reproducible manner. The LC-MS analysis were performed on a C18 and a HILIC type column using electrospray ionization (ESI) with both positive and negative ionization to cover as much of the metabolome as possible. The MarkerLynx software was then used to extract features from the chromatograms. The coefficient of variation (CV) was calculated and the features with CV > 30 % were removed. The features were then used to compare the methods with each other in order to see whether any of the methods yielded the same capture of features. The largest amount of features was detected for precipitation with MeOH when using a C18 type column. For HILIC type columns precipitation with MeOH with a small addition of H3PO4 resulted in most unique features detected. The ionization mode was found to be less important, compared whit the choice of column, but more features was detected using positive mode than negative mode.

  • 114.
    Lampinen Salomonsson, Matilda
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Chemical Derivatization in Combination with Liquid Chromatography Tandem Mass Spectrometry for Detection and Structural Investigation of Glucuronides2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis presents novel approaches for structural investigation of glucuronides using chemical derivatization in combination with liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MSn).

    Today, LC-ESI-MSn is the dominant technique for quantitative as well as qualitative analyses of metabolites, due to its high sensitivity and selectivity. However, for compounds without an easily ionizable group, e.g., steroids, the sensitivity is limited. In the work presented in this thesis, a derivatization procedure forming a basic oxime significantly increased the detection sensitivity for the altrenogest glucuronide.

    Furthermore, in structural evaluations of glucuronides, the limitation of LC-MSn becomes evident due to the initial neutral loss of 176 u, i.e. monodehydrated glucuronic acid, which often makes it impossible to elucidate the structures of the conjugates. To solve this problem, the main part of the work described in this thesis was devoted to chemical derivatization as a means of facilitating the determination of the site of conjugation.

    For the first time, the isomeric estriol glucuronides were evaluated using a combination of three reagents 2-chloro-1-methylpyridinium iodide (CMPI), 1-ethyl-3-(3-dimethyl- aminopropyl)-carbodiimide (EDC), and 2-picolylamine (PA). Interestingly, the derivatization gave a selective fragmentation pattern leading to differentiation of the isomers.

    Another derivatization reagent, 1,2-dimethylimidazole-4-sulfonyl chloride (DMISC), was also tested for the first time in structural investigations. The isomeric glucuronides of morphine, formoterol, and hydroxypropranolol were evaluated. They can all be conjugated in aliphatic as well as aromatic positions. DMISC was proven to be useful in two ways. Firstly, the morphine and formoterol glucuronides that contained a free phenol could be differentiated from those that were conjugated in the aromatic position based on different reactivity. Secondly, for the aromatic O-glucuronide of 4’-hydroxypropranolol, DMISC was proven to react with the amine. This product gave a different fragmentation pattern compared to the corresponding derivative of the aliphatic glucuronide.

    List of papers
    1. Detection of altrenogest and its metabolites in post administration horse urine using liquid chromatography tandem mass spectrometry - Increased sensitivity by chemical derivatization of the glucuronic acid conjugate
    Open this publication in new window or tab >>Detection of altrenogest and its metabolites in post administration horse urine using liquid chromatography tandem mass spectrometry - Increased sensitivity by chemical derivatization of the glucuronic acid conjugate
    2006 In: Journal of Chromatography B, Vol. 833, no 245-256, p. 12-Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-97125 (URN)
    Available from: 2008-04-25 Created: 2008-04-25Bibliographically approved
    2. Differentiation of estriol glucuronide isomers by chemical derivatization and electrospray tandem mass spectrometry
    Open this publication in new window or tab >>Differentiation of estriol glucuronide isomers by chemical derivatization and electrospray tandem mass spectrometry
    2006 In: Rapid Communications in Mass Spectrometry, Vol. 20, no 1429-1440, p. 12-Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-97126 (URN)
    Available from: 2008-04-25 Created: 2008-04-25Bibliographically approved
    3. Structural evaluation of the glucuronides of morphine and formoterol using chemical derivatization with 1,2-Dimethylimidazole-4-sulfonyl chloride and LC-MSn
    Open this publication in new window or tab >>Structural evaluation of the glucuronides of morphine and formoterol using chemical derivatization with 1,2-Dimethylimidazole-4-sulfonyl chloride and LC-MSn
    In: Rapid Communications in Mass SpectrometryArticle in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-97127 (URN)
    Available from: 2008-04-25 Created: 2008-04-25Bibliographically approved
    4. In vitro formation of phase I and II metabolites of propranolol and determination of their structures using chemical derivatization and liquid chromatography tandem mass spectrometry
    Open this publication in new window or tab >>In vitro formation of phase I and II metabolites of propranolol and determination of their structures using chemical derivatization and liquid chromatography tandem mass spectrometry
    2009 (English)In: Journal of Mass Spectrometry, ISSN 1076-5174, E-ISSN 1096-9888, Vol. 44, no 5, p. 742-754Article in journal (Refereed) Published
    Abstract [en]

    Derivatization with 1,2-dimethylimidazole-4-sulfonyl chloride (DMISC)  has been successfully used as a tool to differentiate between aromatic and aliphatic O-glucuronides of hydroxypropranolol. The analyses were   performed with liquid chromatography-electrospray ionization-tandem  mass spectrometry (LC-ESI-MS/MS) with both a triple quadrupole and an   ion trap instrument. Hydroxylated forms of propranolol can be glucuronidated in aliphatic as well as aromatic positions. These isoforms are not distinguishable by tandem MS alone, as they both   initially lose 176 Da, i.e. monodehydrated glucuronic acid, giving back   the aglycone. Two in vitro systems were set up for the production of  propranolol metabolites. The obtained isomers of 4'-hydroxypropranolol   glucuronide were determined to correspond to one aliphatic and one aromatic form, using chemical derivatization with DMISC and LC-MSn. DMISC was shown to react with the secondary amine in the case where the   naphtol was occupied by the glucuronyl moiety, resulting in a different fragmentation pattern compared with that of the aliphatic glucuronide, where the naphtol group was accessible to derivatization.

    Keywords
    derivatization, 1, 2-dimethylimidazole-4-sulfonyl chloride (DMISC), LC-MS/MS, structural investigation, propranolol, glucuronides
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-97128 (URN)10.1002/jms.1551 (DOI)000266681600016 ()
    Available from: 2008-04-25 Created: 2008-04-25 Last updated: 2018-01-13Bibliographically approved
  • 115.
    Lampinen Salomonsson, Matilda
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    In vitro formation of phase I and II metabolites of propranolol and determination of their structures using chemical derivatization and liquid chromatography tandem mass spectrometry2009In: Journal of Mass Spectrometry, ISSN 1076-5174, E-ISSN 1096-9888, Vol. 44, no 5, p. 742-754Article in journal (Refereed)
    Abstract [en]

    Derivatization with 1,2-dimethylimidazole-4-sulfonyl chloride (DMISC)  has been successfully used as a tool to differentiate between aromatic and aliphatic O-glucuronides of hydroxypropranolol. The analyses were   performed with liquid chromatography-electrospray ionization-tandem  mass spectrometry (LC-ESI-MS/MS) with both a triple quadrupole and an   ion trap instrument. Hydroxylated forms of propranolol can be glucuronidated in aliphatic as well as aromatic positions. These isoforms are not distinguishable by tandem MS alone, as they both   initially lose 176 Da, i.e. monodehydrated glucuronic acid, giving back   the aglycone. Two in vitro systems were set up for the production of  propranolol metabolites. The obtained isomers of 4'-hydroxypropranolol   glucuronide were determined to correspond to one aliphatic and one aromatic form, using chemical derivatization with DMISC and LC-MSn. DMISC was shown to react with the secondary amine in the case where the   naphtol was occupied by the glucuronyl moiety, resulting in a different fragmentation pattern compared with that of the aliphatic glucuronide, where the naphtol group was accessible to derivatization.

  • 116.
    Lampinen Salomonsson, Matilda
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Bondesson, Ulf
    Hedeland, Mikael
    Structural evaluation of the glucuronides of morphine and formoterol using chemical derivatization with 1,2-Dimethylimidazole-4-sulfonyl chloride and LC-MSnIn: Rapid Communications in Mass SpectrometryArticle in journal (Refereed)
  • 117.
    Lampinen Salomonsson, Matilda
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Structural evaluation of the glucuronides of morphine and formoterol using chemical derivatization with 1,2-dimethylimidazole-4-sulfonyl chloride and liquid chromatography/ion trap mass spectrometry2008In: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 22, no 17, p. 2685-2697Article in journal (Refereed)
    Abstract [en]

    For the first time chemical derivatization of isomeric drug glucuronides with 1,2-dimethylimidazole-4-sulfonyl chloride (DMISC) has been successfully applied as a tool for determining the site of conjugation. This provides a way to differentiate between glucuronide isomers containing aliphatic and phenolic hydroxyl groups. The analyses were performed with liquid chromatography/electrospray ion trap mass spectrometry (LC/ESI-MSn). DMISC has previously been shown to react selectively with phenols in estrogens, thus improving sensitivity in ESI-MS. The model compounds selected for this study were commercially available standards of formoterol, morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G). Formoterol glucuronides were produced with an enzymatic method in house. Both formoterol and morphine possess one phenolic and one aliphatic hydroxyl group where glucuronidation could take place. The product ion mass spectra of the native morphine glucuronides were indistinguishable due to the initial neutral loss of monodehydrated glucuronic acid (1.76u). However, a significant difference between the isomers was observed with DMISC derivatization, as only the form with a free phenol, M6G, gave a detectable reaction product. Formoterol formed two detectable glucuronide isomers in the enzymatic reaction. Their respective sites of conjugation could not be directly determined from the product ion spectra. Reaction with DMISC, however, gave a detectable product with only one of the isomers. Based on previous experience of the preferred DMISC reactions with phenols, and interpretation of the fragmentation pattern of the derivative, it was concluded that the reactive isomer had a free phenol, and was thus conjugated on the aliphatic chain.

  • 118.
    Lampinen-Salomonsson, Matilda
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Beckman, Elin
    Bondesson, Ulf
    Hedeland, Mikael
    Detection of altrenogest and its metabolites in post administration horse urine using liquid chromatography tandem mass spectrometry - Increased sensitivity by chemical derivatization of the glucuronic acid conjugate2006In: Journal of Chromatography B, Vol. 833, no 245-256, p. 12-Article in journal (Refereed)
  • 119.
    Lampinen-Salomonsson, Matilda
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Bondesson, Ulf
    Petersson, Carl
    Hedeland, Mikael
    Differentiation of estriol glucuronide isomers by chemical derivatization and electrospray tandem mass spectrometry2006In: Rapid Communications in Mass Spectrometry, Vol. 20, no 1429-1440, p. 12-Article in journal (Refereed)
  • 120. Lilienberg, E
    et al.
    Ebeling Barbier, C
    Nyman, C
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Axén, N
    Lennernäs, H
    Local and sustained release in the treatment of primary liver cancer? Pharmacokinetic understanding of two formulations for intra arterial injection2012Conference paper (Other academic)
  • 121. Lilienberg, E
    et al.
    Ebeling Barbier, C
    Nyman, R
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Axén, N
    Lennenrnäs, H
    Improved Pharmacokinetic Understanding of Two Formulations for Intra-arterial Injection2012Conference paper (Other academic)
  • 122. Lilienberg, E
    et al.
    Ebeling Barbier, C
    Nyman, R
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Axén, N
    Lennernäs, H
    Improved Pharmacokinetic Understanding of Two Formulations for Intra-arterial Injection2012Conference paper (Other academic)
  • 123.
    Lilienberg, Elsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Ebeling-Barbier, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Nyman, Rickard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Axén, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernas, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Investigation of Hepatobiliary Disposition of Doxorubicin Following Intrahepatic Delivery of Different Dosage Forms2014In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 11, no 1, p. 131-144Article in journal (Refereed)
    Abstract [en]

    Unresectable, intermediate stage hepatocellular carcinoma (HCC) is often treated palliatively in humans by doxorubicin (DOX). The drug is administered either as a drug-emulsified-in-Lipiodol (DLIP) or as drug loaded into drug eluting beads (DEB), and both formulations are administered intrahepatically. However, several aspects of their in vivo performance in the liver are still not well-understood. In this study, DLIP and DEB were investigated regarding the local and systemic pharmacokinetics (PK) of DOX and its primary metabolite doxorubicinol (DOXol). An advanced PK-multisampling site acute in vivo pig model was used for simultaneous sampling in the portal, hepatic, and femoral veins and the bile duct. The study had a randomized, parallel design with four treatment groups (TI–TIV). TI (n = 4) was used as control and received an intravenous (i.v.) infusion of DOX as a solution. TII and TIII were given a local injection in the hepatic artery with DLIP (n = 4) or DEB (n = 4), respectively. TIV (n = 2) received local injections of DLIP in the hepatic artery and bile duct simultaneously. All samples were analyzed for concentrations of DOX and DOXol with UPLC-MS/MS. Compared to DLIP, the systemic exposure for DOX with DEB was reduced (p < 0.05), in agreement with a slower in vivo release. The approximated intracellular bioavailability of DOX during 6 h appeared to be lower for DEB than DLIP. Following i.v. infusion (55 min), DOX had a liver extraction of 41 (28–53)%, and the fraction of the dose eliminated in bile of DOX and DOXol was 20 (15–22)% and 4.2 (3.2–5.2)%, respectively. The AUCbile/AUCVP for DOX and DOXol was 640 (580–660) and 5000 (3900–5400), respectively. In conclusion, DLIP might initially deliver a higher hepatocellular concentration of DOX than DEB as a consequence of its higher in vivo release rate. Thus, DLIP delivery results in higher intracellular peak concentrations that might correlate with better anticancer effects, but also higher systemic drug exposure and safety issues.

  • 124.
    Lindner, Karl-Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Hartvig, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Åkesson, Christina
    Tyrefors, Niklas
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Långström, Bengt
    Analysis of l-[methyl-11C]methionine and metabolites in human plasma by an automated solid-phase extraction and a high-performance liquid chromatographic procedure1996In: Journal of Chromatography B: Biomedical Sciences and Applications, ISSN 1387-2273, E-ISSN 1878-5603, Vol. 679, no 1-2, p. 13-19Article in journal (Refereed)
    Abstract [en]

    A fully automated method for separation of l-[methyl-11C]Methionine from metabolites in patient plasma was developed. l-[methyl-11C]Methionine was isolated from plasma by solid-phase extraction (SPE). The radioactivity retained on the SPE column was eluted and injected onto the HPLC system for separation of in vivo formed l-[methyl-11C]methionine radiolabeled metabolites. The yield through the isolation procedure and HPLC analysis was greater than 95% with a precision better than 5% (R.S.D.). The calculated rate of l-[methyl-11C]methionine transport into tumor tissue was markedly different with and without compensation for radiolabeled metabolises in patient plasma.

  • 125.
    Liora, Jackson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Characterization of the equine metabolites of LGD-4033 in urine using UHPLC-MS(/MS) for doping control purposes2017Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The aim of this project was to study and characterize the metabolitesof LGD-4033 in equine urine, with the final aim of using the results indoping controls in equestrian sports. Urine samples had been taken atdifferent points in time from three horses that had received thesubstance intravenously. The samples were both directly analysed usinga so called dilute-and-shoot approach and were also prepared with amixed mode anion exchange solid phase extraction. All analysis weredone with UHPLC-ESI-MS(/MS) in negative mode. A total of eightmetabolites were found, which were all combinations of phase Ihydroxylation and/or phase II glucuronidation. Of these a total of four(one that is both monohydroxylated and glucuronidated, one that isdihydroxylated, as well as two glucuronidated metabolites) would besuitable for doping control.

  • 126.
    Liti, Samone
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Evaluation of sample preparation techniques for MALDI-TOF-MS analysis of oligosaccharides2016Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The aim of this study was to optimize the sample preparation and methods for analysis of oligosaccharides of hyaluronic acid with MALDI- TOF-MS. The analysis was carried out on an Autoflex speed MADLI-TOF- MS instrument with both linear and reflectron mode. Matrices used in this study were 2,5-DHB and Super-DHB and type of matrix was chosen depending on the size of the analyzed oligosaccharides. The application of sample and matrix on the target that gave the most homogenous crystallization was sandwich and the laser power in the MALDI was kept at 65 %. Since it is known that salts and buffers interfere with the analysis, sample clean-up such as solid phase extraction (SPE) in pipette tips and dialysis was performed. SPE worked best for low mass oligosaccharides and provided high intensity and little noise. With SPE a concentration of the analyte could be done which was the advantage over dialysis. Dialysis worked well for larger oligosaccharides and mixtures of different sized oligosaccharides. Another way of using MALDI for biomolecule analysis is with TLC-MALDI. A fast and accurate separation was achieved and analysis could be done directly from the plate. The optimized methods were evaluated according to linearity and precision, LOD, mass accuracy and matrix stability. The linearity and precision was good in a higher concentration range (50 μg/mL and higher), but the test for limit-of-detection (LOD) indicated that concentrations from 20-30 μg/mL could be analyzed with no interference from the background. The mass accuracy was within the acceptable limits according to Bruker Daltonics when a mass calibration was done for each analyzed sample. The stability of the matrix in solution was difficult to study because of the day-to-day variation in intensities given by the MALDI-TOF-MS technique. 

  • 127.
    Lodén, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Separation of Pharmaceuticals by Capillary Electrophoresis using Partial Filling and Multiple-injections2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Different multiple-injection methodologies and the partial filling technique (PFT) have been utilized for separation of pharmaceuticals by capillary elec-trophoresis.

    In multiple-injection capillary zone electrophoresis (MICZE), the samples and all standards, used for construction of the calibration curve, are analyzed within a single run. Four different modes of MICZE have been described by means of equations, which were experimentally verified. The developed equations facilitate the transfer from conventional single-injection CZE to one or more of these MICZE-modes, depending on the selectivity between the analyte and the injection marker. The applicability of two of these modes was then demonstrated by quantification of buserelin and salbutamol, re-spectively in commercially available pharmaceutical products. The content of buserelin in an injection solution was determined to 0.94 mg/ml, which only deviated slightly from the declared concentration (1 mg/ml). An alter-native mode of MICZE, offering a higher number of sequential sample injec-tions, was then utilized for single-run determination of salbutamol in 15 tab-lets, with a labelled content of 8 mg. The average content of the tablets was determined to 7.8 mg, with an intra-tablet variation of 3 % or less.

    Moreover, UV- and mass-spectrometric detection of enantiomeric amines, resolved by non-aqueous capillary electrophoresis (NACE), was demon-strated. Separation of enantiomeric amines was achieved using the chiral selector (-)-2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid, (-)-DIKGA. Introduction of the non-volatile (-)-DIKGA into the mass-spectrometer was avoided by using the PFT, where the capillary is only partially filled with electrolyte containing the chiral selector.

    List of papers
    1. Principles for different modes of multiple-injection CZE
    Open this publication in new window or tab >>Principles for different modes of multiple-injection CZE
    2008 (English)In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 29, no 19, p. 3952-3958Article in journal (Refereed) Published
    Abstract [en]

    This paper introduces four different modes of multiple-injection CZE (MICZE). The validity of these MICZE models was evaluated by the experimental data. Prior to the application of MICZE, the electrophoretic conditions are developed in the single-injection mode by adjusting different experimental parameters such as pH, type and concentration of buffer additives and temperature. Based on the migration time difference (tmig) between the analyte and the internal standard or injection marker, one or more MICZE modes can be employed. The injection marker is added to the sample to compensate for injection-volume fluctuations. The inter-plug distance is regulated by applying an electrical field over the capillary for a short period of time between each injection. After the final injection, the separation is completed by electrophoresis for a time period corresponding to that in the single-injection mode

    Place, publisher, year, edition, pages
    Wiley, 2008
    Keywords
    Moxonidine, Multiple-injection, Oxprenolol, Phenylpropanolamine, Salbutamol
    National Category
    Medicinal Chemistry
    Research subject
    Analytical Pharmaceutical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-86740 (URN)10.1002/elps.200800398 (DOI)000261049400002 ()
    Note
    Conference Information: 7th Asia-Pacific International Symposium on Microscale Separations and Analysis Singapore, SINGAPORE, DEC 17-19, 2007 Available from: 2008-12-01 Created: 2008-12-01 Last updated: 2018-01-13Bibliographically approved
    2. Quantification of Buserelin in a Pharmaceutical Product by Multiple-injection CZE
    Open this publication in new window or tab >>Quantification of Buserelin in a Pharmaceutical Product by Multiple-injection CZE
    2007 (English)In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 28, no 10, p. 1548-1556Article in journal (Refereed) Published
    Abstract [en]

    An efficient and rapid separation method based on reversed-polarity multiple-injection CZE (MICZE), has been developed for the quantification of buserelin in a pharmaceutical product. The determinations were performed by serially injecting five standard solutions of buserelin (50-300 μug/mL) and one reference analyte into a Polybrene-coated capillary. All the samples contained goserelin, an analog peptide to buserelin, as internal standard (IS). Immediately after pressure injection, the applied sample plugs were subjected to electrophoresis for 2 min at -25 kV. Consequently, each sample plug became isolated from its neighboring plugs by the BGE, composed of 100 mM phosphate-triethanolamine buffer at pH 3.0 containing 10% v/v ACN. During separation the individual sample components migrated at similar velocities and as distinct zones through the capillary giving 24 peaks, 12 from the analyte and the IS and 12 from the sample matrix. The buserelin content of the pharmaceutical product was determined to be 0.94 ± 0.05 mg/mL, which is only a slight deviation from the declared concentration (1 mg/mL).

    Keywords
    Buserelin, Multiple injection, Peptides, Polybrene, Quantitative analysis
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-97251 (URN)10.1002/elps.200600636 (DOI)000246923300012 ()17447243 (PubMedID)
    Available from: 2008-05-14 Created: 2008-05-14 Last updated: 2018-01-13Bibliographically approved
    3. Determination of Salbutamol in Tablets by Multiple-injection Capillary Zone Electrophoresis
    Open this publication in new window or tab >>Determination of Salbutamol in Tablets by Multiple-injection Capillary Zone Electrophoresis
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-97252 (URN)
    Available from: 2008-05-14 Created: 2008-05-14 Last updated: 2010-01-13Bibliographically approved
    4. Development of a Chiral non-Aqueous Capillary Electrophoretic System using the Partial Filling Technique with UV and Mass Spectrometric Detection
    Open this publication in new window or tab >>Development of a Chiral non-Aqueous Capillary Electrophoretic System using the Partial Filling Technique with UV and Mass Spectrometric Detection
    Show others...
    2003 In: Journal of Chromatography A, ISSN 0021-9673, Vol. 986, no 1, p. 143-152Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-97253 (URN)
    Available from: 2008-05-14 Created: 2008-05-14Bibliographically approved
  • 128.
    Lodén, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Amini, Ahmad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Quantification of Buserelin in a Pharmaceutical Product by Multiple-injection CZE2007In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 28, no 10, p. 1548-1556Article in journal (Refereed)
    Abstract [en]

    An efficient and rapid separation method based on reversed-polarity multiple-injection CZE (MICZE), has been developed for the quantification of buserelin in a pharmaceutical product. The determinations were performed by serially injecting five standard solutions of buserelin (50-300 μug/mL) and one reference analyte into a Polybrene-coated capillary. All the samples contained goserelin, an analog peptide to buserelin, as internal standard (IS). Immediately after pressure injection, the applied sample plugs were subjected to electrophoresis for 2 min at -25 kV. Consequently, each sample plug became isolated from its neighboring plugs by the BGE, composed of 100 mM phosphate-triethanolamine buffer at pH 3.0 containing 10% v/v ACN. During separation the individual sample components migrated at similar velocities and as distinct zones through the capillary giving 24 peaks, 12 from the analyte and the IS and 12 from the sample matrix. The buserelin content of the pharmaceutical product was determined to be 0.94 ± 0.05 mg/mL, which is only a slight deviation from the declared concentration (1 mg/mL).

  • 129. Lodén, Henrik
    et al.
    Hedeland, Ylva
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Hedeland, Mikael
    Bondesson, Ulf
    Pettersson, Curt
    Development of a chiral non-aqueous capillary electrophoretic system using the partial filling technique with UV and mass spectrometric detectionIn: Journal of Chromatography A, ISSN 0021-9673Article in journal (Refereed)
  • 130.
    Lodén, Henrik
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Hedeland, Ylva
    Hedeland, Mikael
    Bondesson, Ulf
    Pettersson, Curt
    Development of a Chiral non-Aqueous Capillary Electrophoretic System using the Partial Filling Technique with UV and Mass Spectrometric Detection2003In: Journal of Chromatography A, ISSN 0021-9673, Vol. 986, no 1, p. 143-152Article in journal (Refereed)
  • 131.
    Lodén, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Hedeland, Ylva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Development of a chiral non-aqueous capillary electrophoretic system using the partial filling technique with UV and mass spectrometric detection2003In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 986, no 1, p. 143-152Article in journal (Refereed)
    Abstract [en]

    A chiral non-aqueous CE system with UV and mass spectrometric detection has been developed. The enantioseparation was promoted by diastereomeric complex (ion-pair) formation between the amines (e.g. salbutamol, atenolol) and the chiral selector, (-)-2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid [(-)-DIKGA]. Different solvent mixtures were studied, as well as different concentrations of (-)-DIKGA and ammonium acetate in the background electrolyte. A partial filling technique was developed with a selector plug composed of (-)-DIKGA and ammonium acetate in a solvent mixture of methanol and 2-propanol. The separated enantiomers of pronethalol were detected by a Q-TOF MS system equipped with a sheath-flow electrospray ionization interface.

  • 132.
    Lodén, Henrik
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Arvidsson, Torbjörn
    Amini, Ahmad
    Determination of Salbutamol in Tablets by Multiple-injection Capillary Zone ElectrophoresisManuscript (Other academic)
  • 133.
    Lodén, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Arvidsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Amini, Ahmad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Quantitative determination of salbutamol in tablets by multiple-injection capillary zone electrophoresis2008In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1207, no 1-2, p. 181-185Article in journal (Refereed)
    Abstract [en]

    A multiple-injection capillary zone electrophoresis (MICZE) method has been developed for the assay of salbutamol in Ventoline Depot tablets (GlaxoSmithKline). In the developed method, seven sample sets, each consisting of three samples, were sequentially injected into the capillary and analyzed within a single run. This enabled a total of twenty-one sequential injections, i.e., six standards and fifteen samples, containing salbutamol and the injection marker oxprenolol. The injected sample plugs were separated by plugs of background electrolyte, through application of a short-term voltage (30 kV) over the capillary for different time periods, i.e., tPE1 and tPE2. The samples in each set were isolated from each other by partial electrophoresis for 2.35 min (tPE1), while the sample sets were separated for 10.50 min (tPE2). After the final injection, all the applied samples were subjected to electrophoresis for a time period corresponding to that in conventional single-injection CZE. The method was validated regarding linearity, accuracy, precision and robustness before it was applied to the determination of salbutamol in 15 tablets of Ventoline Depot with a labeled content of 8 mg salbutamol. The average salbutamol content was determined to 7.8 mg (±0.3 mg) from simultaneous analyses of the 15 different tablets.

  • 134. Lundahl, A
    et al.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Knutson, L
    Lennernäs, H
    Metabolitidentifiering av finasterid i human galla och urin2009Conference paper (Other academic)
  • 135. Lundahl, A
    et al.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Knutson, L
    Lennernäs, H
    The effect of St John’s wort on the pharmacokinetics and metabolism of finasteride in man2008Conference paper (Other academic)
  • 136. Lundahl, A
    et al.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Knutson, L
    Lennernäs, H
    The effect of St John’s Wort treatment on finasteride metabolism and identification of new finasteride metabolites in humans2008Conference paper (Other academic)
  • 137. Lundahl, A
    et al.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Knutson, L
    Lennernäs, H
    The effect of St. John’s wort treatment on finasteride pharmacokinetics and identification of new phase I and phase II metabolites in humans2008Conference paper (Other academic)
  • 138. Lundahl, A
    et al.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Knutsson, L
    Lennernäs, H
    The effect of St John's Wort on the pharmacokinetics and metabolism of finasteride in healthy men2008Conference paper (Other academic)
  • 139. Lundahl, A
    et al.
    Lennernäs, H
    Knutson, L
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Identification of hydroxylated and glucuronidated metabolites of finasteride in human bile and urine2009Conference paper (Other academic)
  • 140. Lundahl, A
    et al.
    Tevell Åberg, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Lennernäs, H
    Metabolite identification by mass spectrometry of the 5α-reductase inhibitor finasteride in vitro and in vivo2009Conference paper (Other academic)
  • 141.
    Lundahl, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Knutson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    The effect of St. John's wort on the pharmacokinetics, metabolism and biliary excretion of finasteride and its metabolites in healthy men2009In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 36, no 4-5, p. 433-443Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate what the consequences of induced drug metabolism, caused by St. John's wort (SJW, Hypericum perforatum) treatment, would have on the plasma, biliary and urinary pharmacokinetics of finasteride and its two previously identified phase I metabolites (hydroxy-finasteride and carboxy-finasteride). Twelve healthy men were administered 5mg finasteride directly to the intestine via a catheter with a multi-channel tubing system, Loc-I-Gut, before and after 14 days SJW (300mg b.i.d, hyperforin 4%) treatment. Bile samples were withdrawn via the Loc-I-Gut device from the proximal jejunum. LC-ESI-MS/MS was used to analyze finasteride and its metabolites in plasma, bile and urine. HPLC-UV was used to analyze hyperforin in plasma. The herbal treatment significantly reduced the peak plasma concentration (C(max)), the area under the plasma concentration-time curve (AUC(0-24h)) and the elimination half-life (t(1/2)) of finasteride. The geometric mean ratios (90% CI) were 0.42 (0.36-0.49), 0.66 (0.56-0.79) and 0.54 (0.48-0.61), respectively. Finasteride was excreted unchanged to a minor extent into bile and urine. Hydroxy-finasteride was not detected in plasma, bile or urine. Carboxy-finasteride was quantified in all three compartments and its plasma pharmacokinetics was significantly affected by SJW treatment. Hyperforin concentration in plasma was 21+/-7ng/ml approximately 12h after the last dose of the 14 days SJW treatment. In conclusion, SJW treatment for 2 weeks induced the metabolism of finasteride and caused a reduced plasma exposure of the drug. New knowledge was gained about the biliary and urinary excretion or the drug and its metabolites.

  • 142.
    Lundahl, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    In Vivo Investigation in Pigs of Intestinal Absorption, Hepatobiliary Disposition, and Metabolism of the 5 alpha-Reductase Inhibitor Finasteride and the Effects of Coadministered Ketoconazole2011In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 39, no 5, p. 847-857Article in journal (Refereed)
    Abstract [en]

    The overall aim of this detailed investigation of finasteride's pharmacokinetics (PK) and metabolism in pigs was to improve the understanding of the in vivo PK for this drug and its metabolites. Specific aims were to examine the effects of ketoconazole co-administration on the PK in three plasma compartments (the portal, hepatic and femoral veins), bile and urine and to utilize these data to in detail study the intestinal absorption, the liver extraction ratio and apply a semi-physiological based PK model to the data. The pigs received an intrajejunal dose of finasteride (0.8 mg/kg) either alone (n=5) or together with ketoconazole (10 mg/kg) (n=5), or an intravenous dose (0.2 mg/kg) (n=3). Plasma, bile and urine (collected from 0-6 hours) were analyzed with ultra performance liquid chromatography tandem mass spectrometry. Ketoconazole increased the bioavailability of finasteride from 0.36±0.23 to 0.91±0.1 (p<0.05) and the terminal half-life from 1.6±0.4 to 4.0±1.1 hours (p<0.05). From deconvolution it was found that the absorption rate from the intestine to the portal vein was rapid and the product of the fraction absorbed and the fraction that escaped gut wall metabolism was high (fa*FG≈1). Interestingly, the apparent absorption rate constant (k(a)) to the femoral vein was lower compared to the portal vein, probably because of binding and distribution within the liver. The liver extraction ratio was time-dependent and varied with the two routes of administration. After intrajejunal administration, from 1 6 hours the liver extraction ratio was significantly (p<0.05) reduced by the ketoconazole treatment from intermediate (0.41±0.21) to low (0.21±0.10).

  • 143.
    Lundahl, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Knutson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Identification of Finasteride Metabolites in Human Bile and Urine by High-Performance Liquid Chromatography/Tandem Mass Spectrometry2009In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 37, no 10, p. 2008-2017Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to further investigate the metabolism of the 5α-reductase inhibitor, finasteride, and to identify previously unknown phase I and phase II metabolites in vitro and in vivo in human bile and urine. Healthy volunteers were given 5 mg of finasteride, directly to the intestine, and bile and urine were collected for 3 and 24 h, respectively. A single-pass perfusion technique, Loc-I-Gut, was used for drug administration and bile collection from the proximal jejunum, distal to papilla of Vater. Incubations with human liver microsomes/S9 fractions and different cofactors were performed with finasteride and the previously known metabolites, ω-hydroxy finasteride (M1) and finasteride-ω-oic acid (M3). Liquid chromatography coupled to triple quadrupole mass spectrometry (MS) with positive/negative electrospray ionization and ion trap with MSn measurements were used for structural investigations and identification of metabolites. Two hydroxy metabolites of finasteride, other than M1, and one intact hydroxy finasteride glucuronide were identified in vitro and in bile and urine. The glucuronide and at least one of the hydroxy metabolites were previously unidentified. M1 and M3 were glucuronidated in vitro by specific human UDP-glucuronosyltransferases, UGT1A4 and UGT1A3, respectively. M1 glucuronide was not identified in vivo, and M3 glucuronide, an acyl glucuronide, was present in low amounts in bile from a few individuals. In conclusion, previously undescribed metabolites were identified, in vitro and in human urine and bile. Bile collection using the Loc-I-Gut technique followed by sensitive mass spectrometry analysis led to the discovery of novel, both phase I and phase II, finasteride metabolites in human bile.

  • 144.
    Lundahl, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Åberg, Annica Tevell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    High-resolution mass spectrometric investigation of the phase I and II metabolites of finasteride in pig plasma, urine and bile2014In: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 44, no 6, p. 498-510Article in journal (Refereed)
    Abstract [en]

    1. The metabolite profile of the 5 alpha-reductase type II inhibitor finasteride has been studied in pig plasma, urine and bile using high-resolution mass spectrometry. The porcine biotransformation products were compared to those formed by human liver microsomes and to literature data of recently identified human in vivo metabolites. The objective of this study was to gain further evidence for the validity of using pigs for advanced, invasive drug-drug interaction studies that are not possible to perform in humans. 2. The use of high-resolution mass spectrometry with accurate mass measurements enabled identification of the metabolites by calculation of their elemental compositions as well as their fragmentation patterns. 3. There was an excellent match between the porcine and human metabolic profiles, corroborating the pig as a model of human drug metabolism. The glucuronides of the two recently described human hydroxylated metabolites MX and MY and the carboxylated metabolite M3 were identified as the major biotransformation products of finasteride in pig urine and bile. 4. Furthermore, the CYP enzymes involved in the formation of the hydroxylated metabolites were characterized. Human recombinant CYP3A4 could produce the two major hydroxylated metabolites MX and MY, whereas human recombinant CYP2D6 formed MY only.

  • 145.
    Lönnberg, Maria
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Cormant, Florence
    L.C.H., Laboratoire des Courses Hippiques, France.
    Garcia, Patrice
    L.C.H., Laboratoire des Courses Hippiques, France.
    Bonnaire, Yves
    L.C.H., Laboratoire des Courses Hippiques, France.
    Carlsson, Jan
    MAIIA Diagnostics, Uppsala, Sweden.
    Popot, Marie-Agnes
    L.C.H., Laboratoire des Courses Hippiques, France.
    Rollborn, Niclas
    MAIIA Diagnostics, Uppsala, Sweden.
    Råsbo, Kristina
    Bailly-Chouriberry, Ludovic
    L.C.H., Laboratoire des Courses Hippiques, France.
    Detection of recombinant human EPO administered to horses using MAIIA lateral flow isoform test2012In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 403, no 6, p. 1619-1628Article in journal (Refereed)
    Abstract [en]

    Doping of horses with recombinant human erythropoietin (rHuEPO) to illegally enhance their endurance capacity in horseracing has been reported during the last years. This leads to increased blood viscosity which can result in sudden death and is of concern for the horse welfare. Additionally, the horse can start production of rHuEPO antibodies, which cross-reacts with endogenous equine EPO and can lead to severe anaemia and even death. In this study, a novel micro-chromatographic method, EPO WGA MAIIA, has been tested for the capability in plasma and urine samples to detect administration of erythropoiesis-stimulating agents, like the rHuEPO glycoprotein varieties Eprex and Aranesp, to horses. After administration of 40 IU Eprex kg −1 day −1 to seven horses during 6 days, the presence of Eprex in horse plasma was detected up to 2–5 days after last injection. In urine samples collected from two horses, Eprex was detected up to 3 days. A single injection of Aranesp (0.39 μg/kg) was detected up to 9 days in plasma and up to 8 days, the last day of testing, in the urine sample. The LC-FAIMS-MS/MS system, with 1 day reporting time, confirmed the presence of Eprex up to 1 day after last injection for six out of seven horses and the presence of Aranesp up to 5 days after last injection in plasma samples. The MAIIA system showed to be a promising tool with high sensitivity and extremely short reporting time (1 h).

  • 146.
    MacMillar, Susanna
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Fang, Yao-ren
    Westaway, Kenneth C.
    Matsson, Olle
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Beronius, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Solvent effects on ion pairing of tetra-n-butylammonium cyanide: A conductometric study2008In: Journal of Physical Organic Chemistry, ISSN 0894-3230, E-ISSN 1099-1395, Vol. 21, no 3, p. 237-241Article in journal (Refereed)
    Abstract [en]

    Tetra-n-butylammonium cyanide (n-Bu4NCN) is a commonly used reagent, for example, for the synthesis of nitriles. Recently n-Bu4NCN has been used as the nucleophilic reagent in kinetic isotope effect studies of nucleophilic aliphatic substitution reactions. The present research concerns the aggregation status (dissociated ions, ion pairs, higher aggregates) and transport properties of n-Bu4NCN in water, dimethyl sulfoxide (DMSO), and tetrahydrofuran (THF), at 25 C as studied by means of precision conductometry. These properties are of great importance since both non-polar and dipolar aprotic solvents are commonly used in the applications. In water as solvent the equilibrium constant for ion-pair formation, K-p =10.1 and the limiting molar conductivity, Lambda(o)= 102.4 cm(2) Omega(-1) mol(-1). The corresponding values for DMSO are K-p =1.98 +/- 0.19 and Lambda(o) = 34.59 +/- 0.03 cm(2) Omega(-1) mol(-1). These data imply that the degree of dissociation, in contrast to the expectations, is higher in DMSO than in water at the same salt concentration. In THF, the conductance as a function of concentration shows a minimum typical for solvents with low relative permittivity, indicating the formation of higher aggregates. The equilibrium constant for ion-pair formation and conductivity in THF is K-p=58.4 X 10(3) and Lambda(o)=9.81 cm(2) Omega(-1) mol(-1).

  • 147. McEwen, Ian
    et al.
    Elmsjö, Albert
    Lehnstrom, Angelica
    Hakkarainen, Birgit
    Johansson, Monika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Screening of counterfeit corticosteroid in creams and ointments by NMR spectroscopy2012In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 70, p. 245-250Article in journal (Refereed)
    Abstract [en]

    It has been shown that NMR spectroscopy is an effective analytical method to rapidly screen creams and ointments for counterfeit corticosteroids. Extraction and NMR procedures have been developed. Ten over the counter creams and ointments sold in health care shops were screened and two creams were found to contain counterfeited corticosteroids.

  • 148.
    Mohabbati, Sheila
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Westerlund, Douglas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Improved properties of the non-covalent coating with N,N-didodecyl-N, N-dimethylammonium bromide for the separation of basic proteins by capillary electrophoresis with acidic buffers in 25mum capillaries2006In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1121, no 1, p. 32-39Article in journal (Refereed)
    Abstract [en]

    Capillaries (25 μm I.D.) treated with the double-alkyl-chain cationic surfactant N,N-didodecyl-N, N-dimethylammonium bromide (DDAB) in an improved coating procedure were used for separation of four basic proteins in volatile buffers (ammonium acetate and ammonium hydroxyacetate) as well as in a non-volatile buffer (sodium phosphate) at pH 4. The DDAB coating was stable enough to, without recoating, permit consecutive separations of the proteins up to 9 h with good precisions in peak areas (RSD = 1.1%) and migration times and with high apparent efficiencies (over 1 million theoretical plates/m) in the presence of a strong anodic electroosmosis. Adsorption of the proteins onto the capillary surface, which in previous studies was found to give a certain contribution to zone broadening, was eliminated with the new modified coating method. Complex formation between the proteins and phosphate buffer was studied and confirmed, and it is proposed that slow protein–buffer component interactions are the main contributions to zone broadening in protein separations by CE.

  • 149.
    Neusüß, Christian
    et al.
    Aalen University.
    Hedeland, Ylva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    CE-MS of Hemoglobins2015Conference paper (Refereed)
  • 150.
    Niklison-Chirou, Maria Victoria
    et al.
    Queen Mary Univ London, Barts & London Sch Med & Dent, Blizard Inst, London E1 2AT, England..
    Erngren, Ida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Engskog, Mikael K R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Haglöf, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Picard, Daniel
    Heinrich Heine Univ Dusseldorf, Dept Pediat Oncol Hematol & Clin Immunol, D-40225 Dusseldorf, Germany.;Heinrich Heine Univ Dusseldorf, Dept Neuropathol, Med Fac, D-40225 Dusseldorf, Germany.;German Canc Consortium DKTK, German Canc Res Ctr DKFZ, Dept Pediat Neurooncogen, D-69120 Heidelberg, Germany..
    Remke, Marc
    Heinrich Heine Univ Dusseldorf, Dept Pediat Oncol Hematol & Clin Immunol, D-40225 Dusseldorf, Germany.;Heinrich Heine Univ Dusseldorf, Dept Neuropathol, Med Fac, D-40225 Dusseldorf, Germany.;German Canc Consortium DKTK, German Canc Res Ctr DKFZ, Dept Pediat Neurooncogen, D-69120 Heidelberg, Germany..
    McPolin, Phelim Hugh Redmond
    Queen Mary Univ London, Barts & London Sch Med & Dent, Blizard Inst, London E1 2AT, England..
    Selby, Matthew
    Newcastle Univ, Wolfson Childhood Canc Res Ctr, Northern Inst Canc Res, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England..
    Williamson, Daniel
    Newcastle Univ, Wolfson Childhood Canc Res Ctr, Northern Inst Canc Res, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England..
    Clifford, Steven C.
    Newcastle Univ, Wolfson Childhood Canc Res Ctr, Northern Inst Canc Res, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England..
    Michod, David
    UCL, Inst Child Hlth, London WC1N 1EH, England..
    Hadjiandreou, Michalis
    Queen Mary Univ London, Barts & London Sch Med & Dent, Blizard Inst, London E1 2AT, England..
    Arvidsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry. Med Prod Agcy, SE-75103 Uppsala, Sweden..
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Melino, Gerry
    Univ Leicester, MRC, Toxicol Unit, Leicester LE1 9HN, Leics, England..
    Marino, Silvia
    Queen Mary Univ London, Barts & London Sch Med & Dent, Blizard Inst, London E1 2AT, England..
    TAp73 is a marker of glutamine addiction in medulloblastoma2017In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 31, no 17, p. 1738-1753Article in journal (Refereed)
    Abstract [en]

    Medulloblastoma is the most common solid primary brain tumor in children. Remarkable advancements in the understanding of the genetic and epigenetic basis of these tumors have informed their recent molecular classification. However, the genotype/phenotype correlation of the subgroups remains largely uncharacterized. In particular, the metabolic phenotype is of great interest because of its druggability, which could lead to the development of novel and more tailored therapies for a subset of medulloblastoma. p73 plays a critical role in a range of cellular metabolic processes. We show overexpression of p73 in a proportion of non-WNT medulloblastoma. In these tumors, p73 sustains cell growth and proliferation via regulation of glutamine metabolism. We validated our results in a xenograft model in which we observed an increase in survival time in mice on a glutamine restriction diet. Notably, glutamine starvation has a synergistic effect with cisplatin, a component of the current medulloblastoma chemotherapy. These findings raise the possibility that glutamine depletion can be used as an adjuvant treatment for p73-expressing medulloblastoma.

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