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Jansson, Britt
Publications (9 of 9) Show all publications
Melander, E., Eriksson, C., Jansson, B., Göransson, U. & Hammarlund-Udenaes, M. (2016). Improved method for quantitative analysis of the cyclotide kalata B1 in plasma and brain homogenate. Paper presented at 3rd International Conference on Circular Proteins (ICCP), NOV 01-04, 2015, AUSTRALIA. Biopolymers, 106(6), 910-916
Open this publication in new window or tab >>Improved method for quantitative analysis of the cyclotide kalata B1 in plasma and brain homogenate
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2016 (English)In: Biopolymers, ISSN 0006-3525, E-ISSN 1097-0282, Vol. 106, no 6, p. 910-916Article in journal, Meeting abstract (Refereed) Published
Abstract [en]

This study provides a new method for quantifying the cyclotide kalata B1 in both plasma and brain homogenate. Cyclotides are ultra-stable peptides with three disulfide bonds that are interesting from a drug development perspective as they can be used as scaffolds. In this study we describe a new validated LC-MS/MS method with high sensitivity and specificity for kalata B1. The limit of quantification was 2 ng/mL in plasma and 5 ng/gmL in brain homogenate. The method was linear in the range 2-10,000 ng/mL for plasma and 5-2000 ng/g for brain. Liquid Chromatographic separation was performed on a HyPurity C18 column, 50 3 4.6 mm, 3 mm particle size. The method had inter-and intra-day precision and accuracy levels <15% and 12% respectively. Applying the method to in vivo plasma samples and brain homogenate samples from equilibrium dialysis yielded satisfying results and was able to describe the plasma pharmacokinetics and brain tissue binding of kalata B1. The described method is quick, reproducible and well suited to quantifying kalata B1 in biological matrices.

Keywords
brain, cyclotides, kalata B1, liquid chromatography, mass spectrometry, pharmacokinetics
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-317707 (URN)10.1002/bip.22984 (DOI)000393465500016 ()27603276 (PubMedID)
Conference
3rd International Conference on Circular Proteins (ICCP), NOV 01-04, 2015, AUSTRALIA
Funder
Swedish Research Council, 2012-5063 2011-4339
Available from: 2017-03-17 Created: 2017-03-17 Last updated: 2018-01-13Bibliographically approved
Loryan, I., Melander, E., Svensson, M., Payan, M., König, F., Jansson, B. & Hammarlund-Udenaes, M. (2016). In-depth neuropharmacokinetic analysis of antipsychotics based on a novel approach to estimate unbound target-site concentration in CNS regions: link to spatial receptor occupancy. Molecular Psychiatry, 21(11), 1527-1536
Open this publication in new window or tab >>In-depth neuropharmacokinetic analysis of antipsychotics based on a novel approach to estimate unbound target-site concentration in CNS regions: link to spatial receptor occupancy
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2016 (English)In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 21, no 11, p. 1527-1536Article in journal (Refereed) Published
Abstract [en]

The current study provides a novel in-depth assessment of the extent of antipsychotic drugs transport across the blood-brain barrier (BBB) into various brain regions, as well as across the blood-spinal cord barrier (BSCB) and the blood-cerebrospinal fluid barrier (BCSFB). This is combined with an estimation of cellular barrier transport and a systematic evaluation of nonspecific brain tissue binding. The study is based on the new Combinatory Mapping Approach (CMA), here further developed for the assessment of unbound drug neuropharmacokinetics in regions of interest (ROI), referred as CMA-ROI. We show that differences exist between regions in both BBB transport and in brain tissue binding. The most dramatic spatial differences in BBB transport were found for the P-glycoprotein substrates risperidone (5.4-fold) and paliperidone (4-fold). A higher level of transporter-mediated protection was observed in the cerebellum compared with other brain regions with a more pronounced efflux for quetiapine, risperidone and paliperidone. The highest BBB penetration was documented in the frontal cortex, striatum and hippocampus (haloperidol, olanzapine), indicating potential influx mechanisms. BSCB transport was in general characterized by more efficient efflux compared with the brain regions. Regional tissue binding was significantly different for haloperidol, clozapine, risperidone and quetiapine (maximally 1.9-fold). Spatial differences in local unbound concentrations were found to significantly influence cortical 5-HT2A receptor occupancy for risperidone and olanzapine. In conclusion, the observed regional differences in BBB penetration may potentially be important factors contributing to variations in therapeutic effect and side effect profiles among antipsychotic drugs.

National Category
Pharmaceutical Sciences Pharmacology and Toxicology
Research subject
Pharmaceutical Pharmacology
Identifiers
urn:nbn:se:uu:diva-277951 (URN)10.1038/mp.2015.229 (DOI)000388719600007 ()26809840 (PubMedID)
Available from: 2016-02-23 Created: 2016-02-23 Last updated: 2018-01-10Bibliographically approved
Lindqvist, A., Jansson, B. & Hammarlund-Udenaes, M. (2012). Quantitative analysis of the opioid peptide DAMGO in rat plasma and microdialysis samples using liquid chromatography-tandem mass spectrometry. Journal of chromatography. B, 900, 11-17
Open this publication in new window or tab >>Quantitative analysis of the opioid peptide DAMGO in rat plasma and microdialysis samples using liquid chromatography-tandem mass spectrometry
2012 (English)In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 900, p. 11-17Article in journal (Refereed) Published
Abstract [en]

A liquid chromatography–electrospray ionization-tandem mass spectrometry (LC–ESI-MS/MS) method for the quantification of the opioid peptide DAMGO in rat plasma, as well as DAMGO and the microdialysis recovery calibrator [13C2,15N]-DAMGO in microdialysis samples, is described. The microdialysis samples consisted of 15 μL Ringer solution containing 0.5% bovine serum albumin. Pretreatment of the samples involved protein precipitation with acetonitrile followed by dilution with 0.01% formic acid. The lower limits of quantification were 0.52 ng/mL and 0.24 ng/mL for DAMGO and [13C2,15N]-DAMGO respectively and the response was linear up to 5000 fold higher concentrations. The plasma samples (50 μL) were precipitated with acetonitrile containing the isotope labeled analog [13C2,15N]-DAMGO as internal standard. The method was linear in the range of 11–110,000 ng/mL. The separations were conducted on a HyPurity C18 column, 50 × 4.6 mm, 3 μm particle size, with a mobile phase consisting of acetonitrile, water and formic acid to the proportions of 17.5:82.5:0.01. Low energy collision dissociation tandem mass spectrometric (CID-MS/MS) analysis was carried out in the positive ion mode using multiple reaction monitoring (MRM) of the following mass transitions: m/z 514.2 → 453.2 for DAMGO and m/z 517.2 → 456.2 for [13C2,15N]-DAMGO. The intra-day precision and accuracy did not exceed 5.2% and 93–104% for both compounds and sample types described. The inter-day precision an accuracy were <6.8% and 95–105% respectively. The method described is simple, reproducible and suitable for the analysis of small sample volumes at low concentrations.

Keywords
Opioid peptide, DAMGO, LC-MS/MS, Microdialysis
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-181430 (URN)10.1016/j.jchromb.2012.05.014 (DOI)000306881000002 ()
Available from: 2012-09-27 Created: 2012-09-24 Last updated: 2018-01-12Bibliographically approved
Sadiq, M. W., Borgs, A., Okura, T., Shimomura, K., Kato, S., Deguchi, Y., . . . Hammarlund-Udenaes, M. (2011). Diphenhydramine Active Uptake at the Blood-Brain Barrier and Its Interaction with Oxycodone in Vitro and in Vivo. Journal of Pharmaceutical Sciences, 100(9), 3912-3923
Open this publication in new window or tab >>Diphenhydramine Active Uptake at the Blood-Brain Barrier and Its Interaction with Oxycodone in Vitro and in Vivo
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2011 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 100, no 9, p. 3912-3923Article in journal (Refereed) Published
Abstract [en]

Diphenhydramine (DPHM) and oxycodone are weak bases that are able to form cations. Both drugs show active uptake at the blood-brain barrier (BBB). There is thus a possibility for a pharmacokinetic interaction between them by competition for the same uptake transport system. The experiments of the present study were designed to study the transport of DPHM across the BBB and its interaction with oxycodone in vitro and in vivo. In vitro, the interaction between the drugs was studied using conditionally immortalized rat brain capillary endothelial cells (TR-BBB13 cells). The in vivo relevance of the in vitro findings was studied in rats using brain and blood microdialysis. DPHM was actively transported across the BBB in vitro (TR-BBB13 cells). Oxycodone competitively inhibited DPHM uptake with a K(i) value of 106 mu M. DPHM also competitively inhibited oxycodone uptake with a K(i) value of 34.7 mu M. In rats, DPHM showed fivefold higher unbound concentration in brain interstitial fluid (ISF) than in blood, confirming a net active uptake. There was no significant interaction between DPHM and oxycodone in vivo. This accords with the results of the in vitro experiments because the unbound plasma concentrations that could be attained in vivo, without causing adverse effects, were far below the Ki values.

Keywords
blood-brain barrier, drug interactions, organic cation transporters (OCTs), pharmacokinetics, active transport, HPLC (high-performance/pressure liquid chromatography), mass spectrometry
National Category
Medical and Health Sciences Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-159250 (URN)10.1002/jps.22567 (DOI)000294666600030 ()
Available from: 2011-09-26 Created: 2011-09-26 Last updated: 2018-01-12Bibliographically approved
Asimus, S., Elsherbiny, D., Hai, T., Jansson, B., Huong, N., Petzold, M., . . . Ashton, M. (2007). Artemisinin antimalarials moderately affect cytochrome P450 enzyme activity in healthy subjects.. Fundamental & Clinical Pharmacology, 21(3), 307-316
Open this publication in new window or tab >>Artemisinin antimalarials moderately affect cytochrome P450 enzyme activity in healthy subjects.
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2007 (English)In: Fundamental & Clinical Pharmacology, ISSN 0767-3981, E-ISSN 1472-8206, Vol. 21, no 3, p. 307-316Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to investigate which principal human cytochrome P450 (CYP450) enzymes are affected by artemisinin and to what degree the artemisinin derivatives differ with respect to their respective induction and inhibition capacity. Seventy-five healthy adults were randomized to receive therapeutic oral doses of artemisinin, dihydroartemisinin, arteether, artemether or artesunate for 5 days (days 1–5). A six-drug cocktail consisting of caffeine, coumarin, mephenytoin, metoprolol, chlorzoxazone and midazolam was administered orally on days −6, 1, 5 and 10 to assess the activities of CYP1A2, CYP2A6, CYP2C19, CYP2D6, CYP2E1 and CYP3A, respectively. Four-hour plasma concentrations of parent drugs and corresponding metabolites and 7-hydroxycoumarin urine concentrations were quantified by liquid chromatography-tandem mass spectrometry. The 1-hydroxymidazolam/midazolam 4-h plasma concentration ratio (CYP3A) was increased on day 5 by artemisinin [2.66-fold (98.75% CI: 2.10–3.36)], artemether [1.54 (1.14–2.09)] and dihydroartemisinin [1.25 (1.06–1.47)] compared with day −6. The S-4'-hydroxymephenytoin/S-mephenytoin ratio (CYP2C19) was increased on day 5 by artemisinin [1.69 (1.47–1.94)] and arteether [1.33 (1.15–1.55)] compared with day −6. The paraxanthine/caffeine ratio (CYP1A2) was decreased on day 1 after administration of artemisinin [0.27 (0.18–0.39)], arteether [0.70 (0.55–0.89)] and dihydroartemisinin [0.73 (0.59–0.90)] compared with day −6. The α-hydroxymetoprolol/metoprolol ratio (CYP2D6) was lower on day 1 compared with day −6 in the artemisinin [0.82 (0.70–0.96)] and dihydroartemisinin [0.83 (0.71–0.96)] groups, respectively. In the artemisinin-treated subjects this decrease was followed by a 1.34-fold (1.14–1.58) increase from day 1 to day 5. These results show that intake of artemisinin antimalarials affect the activities of several principal human drug metabolizing CYP450 enzymes. Even though not significant in all treatment groups, changes in the individual metrics were of the same direction for all the artemisinin drugs, suggesting a class effect that needs to be considered in the development of new artemisinin derivatives and combination treatments of malaria.

Keywords
Artemisinin, cytochrome P450, induction, inhibition, malaria, metabolism
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-96696 (URN)10.1111/j.1472-8206.2007.00471.x (DOI)000246683500010 ()17521300 (PubMedID)
Available from: 2008-02-06 Created: 2008-02-06 Last updated: 2018-01-13Bibliographically approved
Bengtsson, J., Jansson, B. & Hammarlund-Udenaes, M. (2005). On-line desalting and determination of morphine, morphine-3-glucuronide and morphine-6-glucuronide in microdialysis and plasma samples using column switching and liquid chromatography/tandem mass spectrometry. Rapid Communications in Mass Spectrometry, 19(15), 2116-2122
Open this publication in new window or tab >>On-line desalting and determination of morphine, morphine-3-glucuronide and morphine-6-glucuronide in microdialysis and plasma samples using column switching and liquid chromatography/tandem mass spectrometry
2005 (English)In: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 19, no 15, p. 2116-2122Article in journal (Refereed) Published
Abstract [en]

A sensitive and reproducible method for the determination of morphine and the metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) was developed. The method was validated for perfusion fluid used in microdialysis as well as for sheep and human plasma. A C18 guard column was used to desalt the samples before analytical separation on a ZIC HILIC (hydrophilic interaction chromatography) column and detection with tandem mass spectrometry (MS/MS). The mobile phases were 0.05% trifluoroacetic acid (TFA) for desalting and acetonitrile/5 mM ammonium acetate (70:30) for separation. Microdialysis samples (5 microL) were directly injected onto the system. The lower limits of quantification (LLOQ) for morphine, M3G and M6G were 0.50, 0.22 and 0.55 ng/mL, respectively, and the method was linear from LLOQ to 200 ng/mL. For plasma, a volume of 100 microL was precipitated with acetonitrile containing internal standards (deuterated morphine and metabolites). The supernatant was evaporated and reconstituted in 0.05% TFA before the desalting process. The LLOQs for sheep plasma were 2.0 and 3.1 ng/mL and the ranges were 2.0-2000 and 3.1-3100 ng/mL for morphine and M3G, respectively. For human plasma, the LLOQs were 0.78, 1.49 and 0.53 ng/mL and the ranges were 0.78-500, 1.49-1000 and 0.53-500 ng/mL for morphine, M3G and M6G, respectively.

Place, publisher, year, edition, pages
John Wiley & Sons, 2005
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-103231 (URN)10.1002/rcm.2035 (DOI)15988726 (PubMedID)
Available from: 2009-05-15 Created: 2009-05-15 Last updated: 2018-01-13Bibliographically approved
Boström, E., Jansson, B., Hammarlund-Udenaes, M. & Simonsson, U. S. H. (2004). The Use of Liquid Chromatography/Mass Spectrometry for Quantitative Analysis of Oxycodone, Oxymorphone and Noroxycodone in Ringer Solution, Rat Plasma and Rat Brain Tissue. Rapid Communications in Mass Spectrometry, 18(21), 2565-2576
Open this publication in new window or tab >>The Use of Liquid Chromatography/Mass Spectrometry for Quantitative Analysis of Oxycodone, Oxymorphone and Noroxycodone in Ringer Solution, Rat Plasma and Rat Brain Tissue
2004 (English)In: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 18, no 21, p. 2565-2576Article in journal (Refereed) Published
Abstract [en]

Sensitive and reproducible methods for the determination of oxycodone, oxymorphone and noroxycodone in Ringer solution, rat plasma and rat brain tissue by liquid chromatography/mass spectrometry are described. Deuterated analogs of the substances were used as internal standards. Samples in Ringer solution were analyzed by direct injection of 10 microL Ringer solution diluted by an equal volume of water. The limit of quantification was 0.5 ng/mL and the method was linear in the range of 0.5-150 ng/mL for all substances. To analyze oxycodone and oxymorphone in rat plasma, 50 microL of plasma were precipitated with acetonitrile, and the supernatant was directly injected onto the column. To analyze oxycodone, oxymorphone and noroxycodone in rat plasma, 100 microL of rat plasma were subjected to a C18 solid-phase extraction (SPE) procedure, before reconstituting in mobile phase and injection onto the column. For both methods the limit of quantification in rat plasma was 0.5 ng/mL and the methods were linear in the range of 0.5-250 ng/mL for all substances. To analyze the content of oxycodone, oxymorphone and noroxycodone in rat brain tissue, 100 microL of the brain homogenate supernatant were subjected to a C18 SPE procedure. The limit of quantification of oxycodone was 20 ng/g brain, and for oxymorphone and noroxycodone 4 ng/g brain, and the method was linear in the range of 20-1000 ng/g brain for oxycodone and 4-1000 ng/g brain for oxymorphone and noroxycodone. All methods utilized a mobile phase of 5 mM ammonium acetate in 45% acetonitrile, and a SB-CN column was used for separation. The total run time of all methods was 9 min. The intra-day precision and accuracy were <11.3% and <+/-14.9%, respectively, and the inter-day precision and accuracy were <14.9% and <+/-6.5%, respectively, for all the concentrations and matrices described.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-95634 (URN)10.1002/rcm.1658 (DOI)000224872500007 ()15468158 (PubMedID)
Available from: 2007-03-30 Created: 2007-03-30 Last updated: 2018-01-13Bibliographically approved
Simonsson, U. S., Jansson, B., Hai, T. N., Huong, D. X., Tybring, G. & Ashton, M. (2003). Artemisinin autoinduction is caused by involvement of cytochrome P450 2B6 but not 2C9. Clinical Pharmacology and Therapeutics, 74(1), 32-43
Open this publication in new window or tab >>Artemisinin autoinduction is caused by involvement of cytochrome P450 2B6 but not 2C9
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2003 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 74, no 1, p. 32-43Article in journal (Other academic) Published
Abstract [en]

AIM: Our goal was to investigate whether artemisinin autoinduction is caused by an increase in cytochrome P450 (CYP) 2B6 or CYP2C9 activities, we evaluated the effects of multiple-dose artemisinin administration on S-mephenytoin N-demethylation in healthy subjects. METHODS: Fourteen subjects, 6 poor metabolizers of CYP2C19 and 8 extensive metabolizers, received a single oral dose of 200 mg racemic mephenytoin (CYP2B6 in vivo marker) before (day -28) and during multiple-dose artemisinin administration (250 mg/d orally for 9 days and 500 mg on the tenth day). A 500-mg single dose of artemisinin was administered on day -28. The CYP2C9 in vivo marker tolbutamide was administered on day -28 and on days 7, 12, and 17 to monitor the minor involvement of CYP2C9 in S-mephenytoin N-demethylation. RESULTS: Artemisinin oral clearance increased 5.3-fold (P <.001) by the tenth day of administration. Its pharmacokinetics was not different in the 2 CYP2C19 phenotypes. The oral clearance of R-mephenytoin increased 1.7-fold (P <.05) in both phenotypes during the period of artemisinin administration. The area under the concentration-time curve ratio of S-nirvanol/S-mephenytoin, an index of CYP2B6 activity, increased 1.9-fold (P <.05) in CYP2C19 poor metabolizers during artemisinin multiple-dose administration, whereas the urinary excretion ratio of hydroxytolbutamide plus carboxytolbutamide/tolbutamide remained constant during the study period. CONCLUSIONS: These results indicate that artemisinin induces the N-demethylation of S-mephenytoin probably by an increased capacity of CYP2B6. The autoinduction phenomenon of artemisinin may, therefore, be attributed, at least in part, to induction of CYP2B6, because this is the isozyme primarily involved in its metabolism. In addition, artemisinin alters the disposition of R-mephenytoin by an unidentified isozyme.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-72671 (URN)10.1016/S0009-9236(03)00092-4 (DOI)12844133 (PubMedID)
Available from: 2005-05-26 Created: 2005-05-26 Last updated: 2018-01-14Bibliographically approved
Jansson, B., Simonsson, U. S. & Ashton, M. (2003). Simultaneous enantiospecific separation and quantitation of mephenytoin and its metabolites nirvanol and 4'-hydroxymephenytoin in human plasma by liquid chromatography. Journal of chromatography. B, 791(1-2), 179-191
Open this publication in new window or tab >>Simultaneous enantiospecific separation and quantitation of mephenytoin and its metabolites nirvanol and 4'-hydroxymephenytoin in human plasma by liquid chromatography
2003 (English)In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 791, no 1-2, p. 179-191Article in journal (Refereed) Published
Abstract [en]

A high-performance liquid chromatographic method for the enantiospecific quantitation of S- and R-mephenytoin and its metabolites S- and R-nirvanol and S- and R-4'-hydroxymephenytoin in plasma is described. The compounds were separated using a reversed-phase C(2) column in tandem with a chiral alpha(1)-acid glycoprotein column and were detected using ultraviolet detection at 205 nm. The lower limit of quantification was 10 ng/ml for all compounds using 0.5 ml human plasma (intra-day coefficient of variation <13%, accuracy <+/-20%). The method was validated for human plasma in the concentration range 10-2000 ng/ml for each of the six compounds. The method allows for the simultaneous characterisation of the metabolic capacity of two human drug-metabolising enzymes, CYP2C19 and CYP2B6, and may be used when investigating polymorphisms or changes in activity of these two enzymes.

Keywords
mephenytoin, nirvanol, 4 '-hydroxymephenytoin
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-72672 (URN)10.1016/S1570-0232(03)00221-6 (DOI)12798178 (PubMedID)
Available from: 2005-05-26 Created: 2005-05-26 Last updated: 2018-01-14Bibliographically approved
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