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  • 1.
    Adler, Camille
    et al.
    Univ Appl Sci & Arts Northwestern Switzerland, Inst Pharmaceut Technol, CH-4132 Muttenz, Switzerland.;Univ Basel, Inst Pharmaceut Technol, CH-4056 Basel, Switzerland..
    Schoenenberger, Monica
    Swiss Nanosci Inst, Nanotech Serv Lab, CH-4056 Basel, Switzerland..
    Teleki, Alexandra
    DSM Nutr Prod Ltd, Res Ctr Formulat & Applicat, CH-4002 Basel, Switzerland..
    Leuenberger, Bruno
    DSM Nutr Prod Ltd, Res Ctr Formulat & Applicat, CH-4002 Basel, Switzerland..
    Kuentz, Martin
    Univ Appl Sci & Arts Northwestern Switzerland, Inst Pharmaceut Technol, CH-4132 Muttenz, Switzerland..
    Flow-through cross-polarized imaging as a new tool to overcome the analytical sensitivity challenges of a low-dose crystalline compound in a lipid matrix2015In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 115, p. 20-30Article in journal (Refereed)
    Abstract [en]

    Assessing the physical state of a low-dose active compound in a solid lipid or polymer matrix is analytically challenging, especially if the matrix exhibits some crystallinity. The aim of this study was first to compare the ability of current methods to detect the presence of a crystalline model compound in lipid matrices. Subsequently, a new technique was introduced and evaluated because of sensitivity issues that were encountered with current methods. The new technique is a flow-through version of cross-polarized imaging in transmission mode. The tested lipid-based solid dispersions (SDs) consisted of beta-carotene (BC) as a model compound, and of Gelucire 50/13 or Geleol mono- and diglycerides as lipid matrices. The solid dispersions were analyzed by (hyper) differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and microscopic techniques including atomic force microscopy (AFM). DSC and XRPD could analyze crystalline BC at concentrations as low as 3% (w/w) in the formulations. However, with microscopic techniques crystalline particles were detected at significantly lower concentrations of even 0.5% (w/w) BC. A flow-through cross-polarized imaging technique was introduced that combines the advantage of analyzing a larger sample size with high sensitivity of microscopy. Crystals were detected easily in samples containing even less than 0.2% (w/w) BC. Moreover, the new tool enabled approximation of the kinetic BC solubility in the crystalline lipid matrices. As a conclusion, the flow-through cross-polarized imaging technique has the potential to become an indispensable tool for characterizing low-dose crystalline compounds in a lipid or polymer matrix of solid dispersions. (C) 2015 Elsevier B.V. All rights reserved.

  • 2.
    Amini, Ahmad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Identification of ε-caprolactam, melamine and urea in polyvinylpyrrolidone powders by micellar electrokinetic chromatography2014In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 91, p. 12-16Article in journal (Refereed)
    Abstract [en]

    A sodium dodecyl sulfate micellar electrokinetic chromatography (SDS-MEKC) method for the simultaneous separation and identification of ɛ-caprolactam, melamine and urea deliberately added to polyvinylpyrrolidone (povidone) products has been developed. All samples to be analyzed contained paracetamol as an internal marker (IM). The optimized separations were performed in 50 mM phosphate buffer (pH 7.0) containing 2% (w/v) sodium dodecyl sulfate (SDS) in fused silica capillaries with UV absorption detection at 200 nm. The method was validated with respect to repeatability and intermediate precision, selectivity and robustness with satisfactory results. The relative migration times (RMT) were found to be between 0.03% and 0.13% for intra-day precision and between 0.50% and 0.60% for inter-day precision in four days. The detection limits were determined to be 1.3 (11.5 μM), 0.4 (3.5 μM) and 41 μg/ml (0.4 mM) for ɛ-caprolactam, melamine and urea, respectively.

  • 3.
    Amini, Ahmad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Nilsson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Quantitative analysis of polypeptide pharmaceuticals by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry2008In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 46, no 3, p. 411-417Article in journal (Refereed)
    Abstract [en]

    An accurate method based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) has been developed for quantitative analysis of calcitonin and insulin in different commercially available pharmaceutical products. Tryptic peptides derived from these polypeptides were chemically modified at their C-terminal lysine-residues with 2-methoxy-4,5-dihydro-imidazole (light tagging) as standard and deuterated 2-methoxy-4,5-dihydro-imidazole (heavy tagging) as internal standard (IS). The heavy modified tryptic peptides (4D-Lys tag), differed by four atomic mass units from the corresponding light labelled counterparts (4H-Lys tag). The normalized peak areas (the ratio between the light and heavy tagged peptides) were used to construct a standard curve to determine the concentration of the analytes. The concentrations of calcitonin and insulin content of the analyzed pharmaceutical products were accurately determined, and less than 5% error was obtained between the present method and the manufacturer specified values. It was also found that the cysteine residues in CSNLSTCVLGK from tryptic calcitonin were converted to lanthionine by the loss of one sulfhydryl group during the labelling procedure.

  • 4.
    Bekiroglu, Somer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Myrberg, Olle
    Ostman, Kristina
    Ek, Marianne
    Arvidsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Rundlöf, Torgny
    Hakkarainen, Birgit
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Validation of a quantitative NMR method for suspected counterfeit products exemplified on determination of benzethonium chloride in grapefruit seed extracts2008In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 47, no 4-5, p. 958-961Article in journal (Refereed)
    Abstract [en]

    A H-1-nuclear magnetic resonance (NMR) spectroscopy method for quantitative determination of benzethonium chloride (BTC) as a constituent of grapefruit seed extract was developed. The method was validated, assessing its specificity, linearity, range, and precision, as well as accuracy, limit of quantification and robustness. The method includes quantification using an internal reference standard, 1,3,5-trimethoxybenzene, and regarded as simple, rapid, and easy to implement. A commercial grapefruit seed extract was studied and the experiments were performed on spectrometers operating at two different fields, 300 and 600 MHz for proton frequencies, the former with a broad band (BB) probe and the latter equipped with both a BB probe and a CryoProbe (TM). The concentration average for the product sample was 78.0, 77.8 and 78.4 mg/ml using the 300 BB probe, the 600 MHz BB probe and CryoProbe (TM), respectively. The standard deviation and relative standard deviation (R.S.D., in parenthesis) for the average concentrations was 0.2 (0.3%), 0.3 (0.4%) and 0.3 mg/ml (0.4%), respectively.

  • 5.
    Blessborn, Daniel
    et al.
    Dalarna University College, S-781 88 Borlänge, Sweden.
    Neamin, Ghilay
    Dalarna University College, S-781 88 Borlänge, Sweden.
    Bergqvist, Yngve
    Dalarna University College, S-781 88 Borlänge, Sweden.
    Lindegårdh, Niklas
    Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand. Nuffield Department of Clinical Medicine, Centre for Tropical Medicine, University of Oxford, Oxford, UK.
    A new approach to evaluate stability of amodiaquine and its metabolite in blood and plasma.2006In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 41, no 1, p. 207-212Article in journal (Refereed)
    Abstract [en]

    A stability study for amodiaquine (AQ) and desethylamodiaquine (AQm) in whole blood and plasma is reported. AQ, AQm and chloroquine (CQ) were simultaneously analysed and the ratios AQ/CQ and AQm/CQ were used to ensure correct interpretation of the stability results. CQ was stable in whole blood and plasma at all tested temperatures enabling it to be a stability marker in stability studies. Simultaneous analysis of compounds, of which at least one is already known to be stable, permits a within sample ratio to be used as a stability indicator. The new approach significantly reduced bias when compared to the traditional approach. AQ and AQm were stable in plasma at -86 degrees C and -20 degrees C for 35 days, at 4 degrees C for 14 days and at 22 degrees C for 1 day. AQ and AQm were stable in blood at -86 degrees C and 4 degrees C for 35 days, at -20 degrees C and 22 degrees C for 7 days and at 37 degrees C for 1 day.

  • 6.
    Blessborn, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
    Römsing, Susanne
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Center for Clinical Research Dalarna.
    Annerberg, Anna
    Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. Nuffield Department of Clinical Medicine, Centre for Tropical Medicine, University of Oxford, Oxford, UK.
    Sundquist, Daniel
    Dalarna University College, Borlange, Sweden. .
    Björkman, Anders
    Karolinska Institute, Stockholm, Sweden.
    Lindegårdh, Niklas
    Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. Nuffield Department of Clinical Medicine, Centre for Tropical Medicine, University of Oxford, Oxford, UK.
    Bergqvist, Yngve
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
    Development and validation of an automated solid-phase extraction and liquid chromatographic method for determination of lumefantrine in capillary blood on sampling paper2007In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 45, no 2, p. 282-287Article in journal (Refereed)
    Abstract [en]

    A bioanalytical method for the determination of lumefantrine in 100 μl blood applied onto sampling paper, by solid-phase extraction and liquid chromatography, has been developed and validated. Whatman 31 ET Chr sampling paper was pre-treated with 0.75 M tartaric acid before sampling capillary blood to enable a high recovery of lumefantrine. Lumefantrine was extracted from the sampling paper, then further purified using solid-phase extraction and finally quantified with HPLC. The between-day variation was below 10% over the range 0.4-25 μM. The lower limit of quantification was 0.25 μM in 100 μl capillary blood. No decrease in lumefantrine concentration in dried blood spot is seen after 4 months storage at 22 °C. The method was also evaluated in field samples from patients in Tanzania after treatment with lumefantrine/artemether. Lumefantrine could be estimated accurately enough to assess bioavailability and treatment compliance on day 7 (i.e. 4 days after the last dose) after a standard regimen with the lumefantrine/artemether combination.

  • 7. Dehnes, Yvette
    et al.
    Lamon, Severine
    Lönnberg, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
    Erythropoietin (EPO) immunoaffinity columns-A powerful tool for purifying EPO and its recombinant analogues2010In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 53, no 4, p. 1028-1032Article in journal (Refereed)
    Abstract [en]

    The sample preparation method preceding the urinary erythropoietin (EPO) doping test is based on several concentration and ultrafiltration steps. In order to improve the quality of isoelectric focusing (IEF) gel results and therefore, the sensitivity of the EPO test, new sample preparation methods relying on affinity purification were recently proposed. This article focuses on the evaluation and validation of disposable immunoaffinity columns targeting both endogenous and recombinant EPO molecules in two World Anti-Doping Agency (WADA) accredited anti-doping laboratories. The use of the columns improved the resolution of the IEF profiles considerably when compared with the classical ultrafiltration method, and the columns' ability to ensure the isoform integrity of the endogenous and exogenous EPO molecules was confirmed. Immunoaffinity columns constitute therefore a potent and reliable tool for the preparation of urine samples and their use will significantly improve the sensitivity and specificity of the actual urinary EPO test.

  • 8.
    Fabini, Edoardo
    et al.
    Univ Bologna, Dept Pharm & Biotechnol, Via Belmeloro 6, I-40126 Bologna, Italy..
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Monitoring drug-serum protein interactions for early ADME prediction through Surface Plasmon Resonance technology2017In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 144, p. 188-194Article in journal (Refereed)
    Abstract [en]

    Many molecules fail to reach the market due to poor pharmacokinetic (PK) properties, rendering the potential drug virtually unavailable for the primary target despite efficient administration to the body. PK properties of endogenous and exogenous compounds in mammals are dependent, among other factors, on their ability to interact with serum proteins. The extent of binding can greatly influence their ADME (adsorption, distribution, metabolism and execration) profile. Reliable and cost-effective bioavailability studies, early in the drug discovery process, can lead to an improvement of the success rate for compounds entering clinical trials. Optical biosensors based on surface plasmon resonance (SPR) detection emerged as an efficient approach to obtain large amounts of information about the binding of small molecules to serum proteins. Simple, automated and fast assays provide a good throughput, versatility and highly informative data output, rendering the methodology particularly suited for early screening. The ability to provide basic information on PK can be easily coupled to structure-activity relationship analysis. In this review, features of the technology and its employment for the study of serum protein-small molecule interactions are presented and discussed. 

  • 9.
    Hansson, Annelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Thevis, Mario
    German Sport Univ Cologne, Inst Biochem, Cologne, Germany.;German Sport Univ Cologne, Ctr Prevent Doping Res, Cologne, Germany..
    Cox, Holly
    Sports Med Res & Testing Lab, Salt Lake City, UT USA..
    Miller, Geoff
    Sports Med Res & Testing Lab, Salt Lake City, UT USA..
    Eichner, Daniel
    Sports Med Res & Testing Lab, Salt Lake City, UT 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, Dept Chem Environm & Feed Hyg, SE-75189 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, Dept Chem Environm & Feed Hyg, SE-75189 Uppsala, Sweden..
    Investigation of the metabolites of the HIF stabilizer FG-4592 (roxadustat) in five different in vitro models and in a human doping control sample using high resolution mass spectrometry2017In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 134, p. 228-236Article in journal (Refereed)
    Abstract [en]

    FG-4592 is a hypoxia-inducible factor (HIF) stabilizer, which can increase the number of red blood cells in the body. It has not been approved by regulatory authorities, but is available for purchase on the Internet. Due to its ability to improve the oxygen transportation mechanism in the body, FG-4592 is of interest for doping control laboratories, but prior to this study, little information about its metabolism was available. In this study, the metabolism of FG-4592 was investigated in a human doping control sample and in five in vitro models: human hepatocytes and liver microsomes, equine liver microsomes and S9 fraction and the fungus Cunninghamella elegans. By using liquid chromatography coupled to a Q-TOF mass spectrometer operated in MSE and MSMS modes, twelve different metabolites were observed for FG-4592. One monohydroxylated metabolite was detected in both the human and equine liver microsome incubations. For the fungus Cunninghamella elegans eleven different metabolites were observed of which the identical monohydroxylated metabolite had the highest response. This rich metabolic profile and the higher levels of metabolites produced by Cunninghamella elegans demonstrates its usefulness as a metabolite producing medium. In the doping control urine sample, one metabolite, which was the result of a direct glucuronidation, was observed. No metabolites were detected in neither the human hepatocyte nor in the equine liver S9 fraction incubates.

  • 10.
    Jansson, Britt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karvanen, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Plachouras, Diamantis
    Friberg, Lena E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Quantitative analysis of colistin A and colistin B in plasma and culture medium using a simple precipitation step followed by LC/MS/MS2009In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 49, no 3, p. 760-767Article in journal (Refereed)
    Abstract [en]

    An analytical method for quantitation of colistin A and colistin B in plasma and culture medium is described. After protein precipitation with acetonitrile (ACN) containing 0.1% trifluoroacetic acid (TFA), the supernatants were diluted with 0.03% TFA. The compounds were separated on an Ultrasphere C18 column, 4.6 mm x 250 mm, 5 mu m particle size with a mobile phase consisting of 25% ACN in 0.03% TFA and detected with tandem mass spectrometry. The instrument was operating in ESI negative ion mode and the precursor-product ion pairs were m/z 1167.7 -> 1079.6 for colistin A and m/z 1153.7 -> 1065.6 for colistin B. The lower limit of quantification (LLOQ) for 100 mu L plasma was 19.4 and 10.5 ng/mL for colistin A and B, respectively, with CV <6.2% and accuracy <+/- 12.6%. For culture medium (50 mu L+ 50 mu L plasma), LLOQ was 24.2 and 13.2 ng/mL for colistin A and B, respectively, with CV <11.4% and accuracy <+/- 8.1%. The quick sample work-up method allows for determination of colistin A and B in clinical samples without causing hydrolysis of the prodrug colistin methanesulfonate (CMS).

  • 11.
    Johannesson, Nina
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry.
    Rapid on-line extraction and quantification of escitalopram from urine using sol-gel columns and mass spectrometric detection2007In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 43, no 3, p. 1045-1048Article in journal (Refereed)
    Abstract [en]

    A fast and easy way to quantify escitalopram in urine has been developed. A capillary with a silica based monolithic bed inside is used to extract escitalopram from urine and the for mass spectrometry detrimental matrix is washed away by applied pressure. The analyte is eluted by a solution containing organic modifier and directly electrosprayed into a time-of-flight mass spectrometer, ESI-TOF-MS. This method makes it possible to load large volumes of sample onto the column and preconcentrate escitalopram on-line before detection. Standard addition of escitalopram to the urine sample gave a linear calibration curve (R2 = 0.988). The analyzed sample was found to contain an escitalopram concentration of 0.62 ng/ml, well in line with earlier publications. The calculated LOD was 10 pg/ml and LOQ was 34 pg/ml as compared to earlier reports with a LLOQ of 1 ng/ml. The intra day variation of the escitalopram peak area is less than 6.3%.

  • 12.
    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.

  • 13. Josefsson, Martin
    et al.
    Roman, Markus
    Skogh, Elisabeth
    Dahl, Marja-Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Liquid chromatography/tandem mass spectrometry method for determination of olanzapine and N-desmethylolanzapine in human serum and cerebrospinal fluid2010In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 53, no 3, p. 576-582Article in journal (Refereed)
    Abstract [en]

    A validated, accurate and sensitive LC-MS/MS method for determination of olanzapine and its metabolite N-desmethylolanzapine has been developed. The analytes were quantified by tandem mass spectrometry operating in positive electrospray ionization mode with multiple reaction monitoring Olanzapine and desmethylolanzapine were extracted from serum or cerebral spinal fluid samples, 200 mu l, with tert-butyl methyl ether using olanzapine-D3 as internal standard Calibrations for olanzapine and desmethylolanzapine were linear within the selected range of 0.2-30 ng/ml (6-96 nM) in cerebral spinal fluid and for olanzapine in plasma, in the range of 5-100 ng/ml (16-320 nM) The method was successfully used for the analysis of samples from patients treated with olanzapine in the dose range of 2.5-25 mg/day.

  • 14.
    Kip, A E
    et al.
    Slotervaart Hosp, Antoni van Leeuwenhoek Hosp, Dept Pharm & Pharmacol, POB 90440, NL-1006 BK Amsterdam, Netherlands.; Univ Utrecht, Fac Sci, Utrecht Inst Pharmaceut Sci, Div Pharmacoepidemiol & Clin Pharmacol, Univ Weg 99, NL-3584 CG Utrecht, Netherlands.
    Kiers, K C
    Slotervaart Hosp, Antoni van Leeuwenhoek Hosp, Dept Pharm & Pharmacol, POB 90440, NL-1006 BK Amsterdam, Netherlands.
    Rosing, H
    Slotervaart Hosp, Antoni van Leeuwenhoek Hosp, Dept Pharm & Pharmacol, POB 90440, NL-1006 BK Amsterdam, Netherlands.
    Schellens, J H M
    Univ Utrecht, Fac Sci, Utrecht Inst Pharmaceut Sci, Div Pharmacoepidemiol & Clin Pharmacol, Univ Weg 99, NL-3584 CG Utrecht, Netherlands.; Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Dept Clin Pharmacol, POB 90203, NL-1006 BE Amsterdam, Netherlands.
    Beijnen, J H
    Slotervaart Hosp, Antoni van Leeuwenhoek Hosp, Dept Pharm & Pharmacol, POB 90440, NL-1006 BK Amsterdam, Netherlands.; Univ Utrecht, Fac Sci, Utrecht Inst Pharmaceut Sci, Div Pharmacoepidemiol & Clin Pharmacol, Univ Weg 99, NL-3584 CG Utrecht, Netherlands.; Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Dept Clin Pharmacol, POB 90203, NL-1006 BE Amsterdam, Netherlands.
    Dorlo, Thomas P C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Univ Utrecht, Fac Sci, Utrecht Inst Pharmaceut Sci, Div Pharmacoepidemiol & Clin Pharmacol, Univ Weg 99, NL-3584 CG Utrecht, Netherlands.
    Volumetric absorptive microsampling (VAMS) as an alternative to conventional dried blood spots in the quantification of miltefosine in dried blood samples.2017In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 135, p. 160-166Article in journal (Refereed)
    Abstract [en]

    Miltefosine is an oral agent against the neglected tropical disease leishmaniasis, which is mostly endemic in resource-poor areas. Dried blood spot (DBS) sampling is an attractive alternative to plasma sampling for pharmacokinetic studies in these remote areas, but introduces additional variability in analyte quantification due to possible blood spot inhomogeneity and variability in blood spot volume and haematocrit values. Volumetric absorptive microsampling (VAMS) potentially overcomes a few of these issues as the VAMS device absorbs a fixed volume that is processed as a whole. We developed and validated an LC-MS/MS method for the quantification of miltefosine with this novel sampling technique with good performance in terms of linearity, selectivity, accuracy (bias within ±10.8%), precision (CV%≤11.9%), recovery, carry-over and matrix effect. VAMS samples were stable for at least one month at room temperature and 37°C. The impact of haematocrit on assay accuracy was reduced compared to conventional DBS sampling, but indicated a declining recovery with increased haematocrit due to haematocrit dependency in recovery from the sampling device. A clinical validation will be required to investigate whether VAMS is an appropriate and cost-effective alternative sampling method to conventional DBS sampling.

  • 15.
    Lindegårdh, Niklas
    et al.
    Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand; Nuffield Department of Clinical Medicine, Centre for Tropical Medicine, University of Oxford, Oxford, UK.
    Annerberg, Anna
    Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand.
    Blessborn, Daniel
    Dalarna University College, S-781 88 Borlänge, Sweden.
    Bergqvist, Yngve
    Dalarna University College, S-781 88 Borlänge, Sweden.
    Day, Nicholas PJ
    Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand; Nuffield Department of Clinical Medicine, Centre for Tropical Medicine, University of Oxford, Oxford, UK.
    White, Nicholas J
    Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand; Nuffield Department of Clinical Medicine, Centre for Tropical Medicine, University of Oxford, Oxford, UK.
    Development and validation of a bioanalytical method using automated solid-phase extraction and LC-UV for the simultaneous determination of lumefantrine and its desbutyl metabolite in plasma2005In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 37, no 5, p. 1081-1088Article in journal (Refereed)
    Abstract [en]

    A bioanalytical method for the determination of lumefantrine (LF) and its metabolite desbutyl-lumefantrine (DLF) in plasma by solid-phase extraction (SPE) and liquid chromatography has been developed. Plasma proteins were precipitated with acetonitrile:acetic acid (99:1, v/v) containing a DLF analogue internal standard before being loaded onto a octylsilica (3 M Empore) SPE column. Two different DLF analogues were evaluated as internal standards. The compounds were analysed by liquid chromatography UV detection on a SB-CN (250 mm x 4.6 mm) column with a mobile phase containing acetonitrile-sodium phosphate buffer pH (2.0; 0.1 M) (55:45, v/v) and sodium perchlorate 0.05 M. Different SPE columns were evaluated during method development to optimise reproducibility and recovery for LF, DLF and the two different DLF analogues. The within-day precisions for LF were 6.6 and 2.1% at 0.042 and 8.02 microg/mL, respectively, and for DLF 4.5 and 1.5% at 0.039 and 0.777 microg/mL, respectively. The between-day precisions for LF were 12.0 and 2.9% at 0.042 and 8.02 microg/mL, respectively, while for DLF 0.7 and 1.2% at 0.039 and 0.777 microg/mL, respectively. The limit of quantification was 0.024 and 0.021 microg/mL for LF and DLF, respectively. Different amounts of lipids in plasma did not affect the absolute recovery of LF or DLF.

  • 16.
    Lönnberg, Maria
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Garle, Mats
    Doping Control Laboratory, Karolinska University Hospital, Stockholm, Sweden.
    Lönnberg, Lina
    Department of Ecology, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Birgegård, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Patients with anaemia can shift from kidney to liver production of erythropoietin as shown by glycoform analysis2013In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 81-82, p. 187-192Article in journal (Refereed)
    Abstract [en]

    The primary production site of erythropoietin (EPO) is shifted from the liver to the kidney shortly after birth. Under conditions of lost or reduced kidney production, it is valuable to measure the production capacity of the liver. However, there is a lack of urine or serum based methods that can distinguish endogenous EPO produced in different cell types. Here is presented a method based on chromatographic interaction with the lectin wheat germ agglutinin (WGA) that can distinguish presumably liver-produced EPO, found in anaemic patients receiving epoetin and darbepoetin, from kidney-produced EPO found in healthy individuals.

    All the tested samples from haemodialysis patients with end-stage renal disease showed a presence of liver EPO. In some samples, the liver-produced EPO made up 90–100% of total EPO at a concentration of 8–10 ng/L in urine, which indicates that the liver has a quite high production capacity, although not adequate for the degree of anaemia.

    This glycoform analysis has made it possible to affirm that some anaemic patients can increase their liver-production of EPO. The use of such a method can give better insight into the regulation of non-renal endogenous EPO production, a potential source of EPO intended to replace administration of exogenous EPO.

  • 17. 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.

  • 18.
    Paul, Prasanta
    et al.
    KU Leuven Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Pharmaceut Anal, O&N2, PB 923,Herestr 49, B-3000 Leuven, Belgium..
    Sänger - van de Griend, Cari
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Science. Kantisto BV, Callenburglaan 22, NL-3742 MV Baarn, Netherlands..
    Adams, Erwin
    KU Leuven Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Pharmaceut Anal, O&N2, PB 923,Herestr 49, B-3000 Leuven, Belgium..
    Van Schepdael, Ann
    KU Leuven Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Pharmaceut Anal, O&N2, PB 923,Herestr 49, B-3000 Leuven, Belgium..
    Recent advances in the capillary electrophoresis analysis of antibiotics with capacitively coupled contactless conductivity detection2018In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 158, p. 405-415Article, review/survey (Refereed)
    Abstract [en]

    This review describes briefly the high rate of counterfeiting of antimicrobial drugs with focus upon its immediate health consequences. The major part of this review encompasses accounts of the improvements achieved in the domain of miniaturization of capillary electrophoresis with capacitively coupled contactless conductivity detection (CE-(CD)-D-4). The application of this principle into the development of portable devices as well as its application to counter the health-system-crippling phenomenon of counterfeit antibiotic formulations, are discussed in the context of developing countries. 

  • 19.
    Prasanta, Paul
    et al.
    KU Leuven Univ Leuven, Pharmaceut Anal, Dept Pharmaceut & Pharmacol Sci, O&N2,PB 923,Herestr 49, B-3000 Leuven, Belgium.
    Van Laeken, Christophe
    KU Leuven Univ Leuven, Pharmaceut Anal, Dept Pharmaceut & Pharmacol Sci, O&N2,PB 923,Herestr 49, B-3000 Leuven, Belgium.
    Sänger-van de Griend, Cari
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry. Kantisto BV, Callenburglaan 22, NL-3742 MV Baarn, Netherlands.
    Adams, Erwin
    KU Leuven Univ Leuven, Pharmaceut Anal, Dept Pharmaceut & Pharmacol Sci, O&N2,PB 923,Herestr 49, B-3000 Leuven, Belgium.
    Van Schepdael, Ann
    KU Leuven Univ Leuven, Pharmaceut Anal, Dept Pharmaceut & Pharmacol Sci, O&N2,PB 923,Herestr 49, B-3000 Leuven, Belgium.
    CE-C4D method development and validation for the assay of ciprofloxacin2016In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 129, p. 1-8Article in journal (Refereed)
    Abstract [en]

    A capillary electrophoresis method with capacitively coupled contactless conductivity detection (CE-C(4)D) has been developed, optimized and validated for the determination of ciprofloxacin. Ciprofloxacin is a member of the fluoroquinolone antibiotics with a broad spectrum bactericidal activity and recommended for complicated respiratory infections, sexually transmitted diseases, tuberculosis, bacterial diarrhea etc. Method development was conducted with major focus on the quality by design (QbD) approach. During method development, multiple buffers were tried at different ionic strength. However, the optimized method finally involved a very simple background electrolyte, monosodium citrate at a concentration of 10mM without pH adjustment. The optimized CE-C(4)D method involved an uncoated fused silica capillary (59/39cm, 50μm i.d.) and hydrodynamic sample injection at a pressure of 0.5 p.s.i. for 5s. The actual separation was conducted for 10min at normal polarity with a voltage of 20kV corresponding to 5.9μA current. LiCl (1mg/mL) was used as an internal standard. The optimized method is robust and accurate (recovery >98%) which rendered the ciprofloxacin peak within five minutes with good linearity (R(2)>0.999) in the concentration range of 0.0126-0.8mg/mL. The repeatability is expressed by percentage relative standard deviation (%RSD) of the relative peak areas (RPA) and it showed good repeatability both intra-day (<3%) and inter-day (3.1%). This method, proven to be free of matrix interference, showed that the estimated percent content of ciprofloxacin (102%) was within the official requirements. Moreover, due to its ease of use and robustness, the method should also be applicable in less well controlled laboratory environments.

  • 20. Rundlöf, Torgny
    et al.
    Mathiasson, Marie
    Bekiroglu, Somer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Hakkarainen, Birgit
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Bowden, Tim
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Arvidsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Survey and qualification of internal standards for quantification by 1H NMR spectroscopy2010In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 52, no 5, p. 645-651Article in journal (Refereed)
    Abstract [en]

    In quantitative NMR (qNMR) selection of an appropriate internal standard proves to be crucial. In this study, 25 candidate compounds considered to be potent internal standards were investigated with respect to the ability of providing unique signal chemical shifts, purity, solubility, and ease of use. The 1H chemical shift (δ) values, assignments, multiplicities and number of protons (for each signal), appropriateness (as to be used as internal standards) in four different deuterated solvents (D2O, DMSO-d6, CD3OD, CDCl3) were studied. Taking into account the properties of these 25 internal standards, the most versatile eight compounds (2,4,6-triiodophenol, 1,3,5-trichloro-2-nitrobenzene, 3,4,5-trichloropyridine, dimethyl terephthalate, 1,4-dinitrobenzene, 2,3,5-triiodobenzoic acid, maleic acid and fumaric acid) were qualified using both differential scanning calorimetry (DSC) and NMR spectroscopy employing highly pure acetanilide as the reference standard. The data from these two methods were compared as well as utilized in the quality assessment of the compounds as internal standards. Finally, the selected internal standards were tested and evaluated in a real case of quantitative NMR analysis of a paracetamol pharmaceutical product.

  • 21. Rundlöf, Torgny
    et al.
    McEwen, Ian
    Johansson, Monika
    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.
    Use and qualification of primary and secondary standards employed in quantitative H-1 NMR spectroscopy of pharmaceuticals2014In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 93, no SI, p. 111-117Article in journal (Refereed)
    Abstract [en]

    Standards are required in quantitative NMR (qNMR) to obtain accurate and precise results. In this study acetanilide was established and used as a primary standard. Six other chemicals were selected as secondary standards: 3,4,5-trichloropyridine, dimethylterephthalate, maleic acid, 3-sulfolene, 1,4-bis(trimethylsilyl)benzene, and 1,3,5-trimethoxybenzene. The secondary standards were quantified using the primary standard acetanilide. A protocol for qualification and periodic checks of these secondary standards was developed, and used for evaluation of the stability of the compounds. Periodic monitoring of purity was performed for several years. The purity was higher than 99% for all secondary standards. All standards maintained the initial purity during the time period of monitoring, with very small variations in purity (0.3-0.4%). The selected secondary standards were shown to be suitable qNMR standards and that periodic requalification of the standards by qNMR ensures reliable analytical results. These standards have been used in our laboratory for compliance testing of pharmaceutical active substances and approved medicinal products as well as for analysis of suspected illegal medicines. In total more than 1000 samples have been tested using both internal and external standardization and examples are given.

  • 22.
    Rydevik, Axel
    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.
    Thevis, Mario
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Mass spectrometric characterization of glucuronides formed by a new concept, combining Cunninghamella elegans with TEMPO2013In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 84, p. 278-284Article in journal (Refereed)
    Abstract [en]

    A new concept for the production of drug glucuronides is presented and the products formed were characterized using ultra high performance liquid chromatography-high resolution mass spectrometry (UPLC-HRMS). Glucuronic acid conjugates are important phase II metabolites of a wide range of drugs. There is a lack of commercially available glucuronides and classic synthetic methods are tedious and expensive. Thus, new methods of glucuronide synthesis are needed. Selective androgen receptor modulators (SARMs) of the aryl propionamide class were used as model compounds and were incubated with the fungus Cunninghamella elegans which was previously known to conjugate drugs with glucose. The resulting glucoside metabolites were then oxidized with tetramethylpiperidinyl-1-oxy (TEMPO). UPLC-HRMS analysis showed that the peaks corresponding to the glucosides had disappeared after the reaction and were replaced by peaks with m/z consistent with the corresponding glucuronic acid conjugates. The MS/MS spectra of the reaction products were investigated and the observed fragment ion pattern corroborated the suggested structural change. A comparison in terms of retention times and product ion spectra between the glucuronides formed by the new method and those produced by liver microsomes indicated that the conjugates from the two different sources were identical, thus demonstrating the human relevance of the presented technique. Furthermore, the glucuronides formed by the presented method were readily hydrolyzed by β-glucuronidase which further gave evidence as to the fact that they were of β configuration. The investigated method was easy to perform, required a low input of work and had a low cost.

  • 23.
    Rydevik, Axel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Lagojda, Andreas
    Bayer CropScience AG.
    Thevis, Mario
    Institute of Biochemistry and Center for Preventive Doping Research, German Sport University, Cologne.
    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.
    Isolation and characterization of a beta-glucuronide of hydroxylated SARM S1 produced using a combination of biotransformation and chemical oxidation2014In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 98, p. 36-39Article in journal (Refereed)
    Abstract [en]

    In this study, using mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy, it has been confirmed that biotransformation with the fungus Cunninghamella elegans combined with chemical oxidation with the free radical tetramethylpiperidinyl-1-oxy (TEMPO) can produce drug glucuronides of beta-configuration. Glucuronic acid conjugates are a common type of metabolites formed by the human body. The detection of such conjugates in doping control and other kinds of forensic analysis would be beneficial owing to a decrease in analysis time as hydrolysis can be omitted. However the commercial availability of reference standards for drug glucuronides is poor. The selective androgen receptor modulator (SARM) SARM Si was incubated with the fungus C elegans. The sample was treated with the free radical TEMPO oxidizing agent and was thereafter purified by SPE. A glucuronic acid conjugate was isolated using a fraction collector connected to an ultra high performance liquid chromatographic (UHPLC) system. The isolated compound was characterized by NMR spectroscopy and mass spectrometry and its structure was confirmed as a glucuronic acid beta-conjugate of hydroxylated SARM Si bearing the glucuronide moiety on carbon C-10.

  • 24. Salas, Emir
    et al.
    Ramirez, Angel
    Otero, Anabel
    Vazquez, Rayner
    Reyes, Osvaldo
    Mendiola, Judith
    Duarte, Carlos
    Otero, Anselmo
    Gutierrez Arenas, Omar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Chavez, Maria de los Angeles
    A heterogeneous enzymatic assay for quantification of Plasmepsin II activity and the evaluation of its inhibitors2004In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264XArticle in journal (Refereed)
  • 25. Tretzel, Laura
    et al.
    Thomas, Andreas
    Piper, Thomas
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Geyer, Hans
    Schänzer, Wilhelm
    Thevis, Mario
    Fully automated determination of nicotine and its major metabolites in whole blood by means of a DBS online-SPE LC-HR-MS/MS approach for sports drug testing2016In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 123, p. 132-140Article in journal (Refereed)
    Abstract [en]

    Dried blood spots (DBS) represent a sample matrix collected under minimal-invasive, straightforward and robust conditions. DBS specimens have been shown to provide appropriate test material for different analytical disciplines, e.g., preclinical drug development, therapeutic drug monitoring, forensic toxicology and diagnostic analysis of metabolic disorders in newborns. However, the sample preparation has occasionally been reported as laborious and time consuming. In order to minimize the manual workload and to substantiate the suitability of DBS for high sample-throughput, the automation of sample preparation processes is of paramount interest. In the current study, the development and validation of a fully automated DBS extraction method coupled to online solid-phase extraction using the example of nicotine, its major metabolites nornicotine, cotinine and trans-3′-hydroxycotinine and the tobacco alkaloids anabasine and anatabine is presented, based on the rationale that the use of nicotine-containing products for performance-enhancing purposes has been monitored by the World Anti-Doping Agency (WADA) for several years. Automation-derived DBS sample extracts were directed online to liquid chromatography high resolution/high mass accuracy tandem mass spectrometry, and target analytes were determined with support of four deuterated internal standards. Validation of the method yielded precise (CV <7.5% for intraday and <12.3% for interday measurements) and linear (r2 > 0.998) results. The limit of detection was established at 5 ng mL−1 for all studied compounds, the extraction recovery ranged from 25 to 44%, and no matrix effects were observed. To exemplify the applicability of the DBS online-SPE LC–MS/MS approach for sports drug testing purposes, the method was applied to authentic DBS samples obtained from smokers, snus users, and e-cigarette users. Statistical evaluation of the obtained results indicated differences in metabolic behavior depending on the route of administration (inhalative versus buccal absorption) in terms of the ratio of nicotine and nornicotine.

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