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  • 1.
    Chen, Xiaomei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Loryan, Irena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Payan, Maryam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Keep, Richard
    Smith, David E
    Margareta, Hammarlund-Udenaes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Effect of transporter inhibition on the distribution of cefadroxil in rat brain2014In: Fluids and Barriers of the CNS, ISSN 2045-8118, E-ISSN 2045-8118, Vol. 11, article id 25Article in journal (Refereed)
    Abstract [en]

    Background

    Cefadroxil, a cephalosporin antibiotic, is a substrate for several membrane transporters including peptide transporter 2 (PEPT2), organic anion transporters (OATs), multidrug resistance-associated proteins (MRPs), and organic anion transporting polypeptides (OATPs). These transporters are expressed at the blood-brain barrier (BBB), blood-cerebrospinal fluid barrier (BCSFB), and/or brain cells. The effect of these transporters on cefadroxil distribution in brain is unknown, especially in the extracellular and intracellular fluids within brain.

    Methods

    Intracerebral microdialysis was used to measure unbound concentrations of cefadroxil in rat blood, striatum extracellular fluid (ECF) and lateral ventricle cerebrospinal fluid (CSF). The distribution of cefadroxil in brain was compared in the absence and presence of probenecid, an inhibitor of OATs, MRPs and OATPs, where both drugs were administered intravenously. The effect of PEPT2 inhibition by intracerebroventricular (icv) infusion of Ala-Ala, a substrate of PEPT2, on cefadroxil levels in brain was also evaluated. In addition, using an in vitro brain slice method, the distribution of cefadroxil in brain intracellular fluid (ICF) was studied in the absence and presence of transport inhibitors (probenecid for OATs, MRPs and OATPs; Ala-Ala and glycylsarcosine for PEPT2).

    Results

    The ratio of unbound cefadroxil AUC in brain ECF to blood (Kp,uu,ECF) was ~2.5-fold greater during probenecid treatment. In contrast, the ratio of cefadroxil AUC in CSF to blood (Kp,uu,CSF) did not change significantly during probenecid infusion. Icv infusion of Ala-Ala did not change cefadroxil levels in brain ECF, CSF or blood. In the brain slice study, Ala-Ala and glycylsarcosine decreased the unbound volume of distribution of cefadroxil in brain (Vu,brain), indicating a reduction in cefadroxil accumulation in brain cells. In contrast, probenecid increased cefadroxil accumulation in brain cells, as indicated by a greater value for Vu,brain.

    Conclusions

    Transporters (OATs, MRPs, and perhaps OATPs) that can be inhibited by probenecid play an important role in mediating the brain-to-blood efflux of cefadroxil at the BBB. The uptake of cefadroxil in brain cells involves both the influx transporter PEPT2 and efflux transporters (probenecid-inhibitable). These findings demonstrate that drug-drug interactions via relevant transporters may affect the distribution of cephalosporins in both brain ECF and ICF.

  • 2. Choong, Eva
    et al.
    Loryan, Irena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Karolinska Institutet, Yerevan State Medical University.
    Lindqvist, Marja
    Nordling, Åsa
    el Bouazzaoui, Samira
    van Schaik, Ron H
    Johansson, Inger
    Jakobsson, Jan
    Ingelman-Sundberg, Magnus
    Sex difference in formation of propofol metabolites: a replication study2013In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 113, no 2, p. 126-131Article in journal (Refereed)
    Abstract [en]

    Women recover faster from propofol anaesthesia and have been described to have a higher incidence of awareness during surgery, compared to men - an effect that may be inherent in sex differences in propofol metabolism. In an observational study, 98 ASA I-II patients treated with continuous propofol infusion were recruited. The associations between sex and CYP2B6 and UGT1A9 polymorphisms with dose- and weight-adjusted area under the total plasma level time curves (AUC) for propofol, and its metabolites propofol glucuronide (PG), 4-hydroxypropofol (OHP) and hydroxyl glucuronide metabolites 4-hydroxypropofol-1-O-β-D-glucuronide (Q1G) and 4-hydroxypropofol-4-O-β-D-glucuronide (Q4G), were analysed. Significantly higher AUC of PG (1.3 times, p = 0.03), Q1G (2.9 times, p < 0.001), Q4G (2.4 times, p < 0.01) and OHP (4.6 times, p = 0.01) were found in women (n = 53) than in men (n = 45) after intravenous infusion of propofol using target-controlled infusion system. There was, however, no significant impact of gene polymorphisms on propofol biotransformation. The results, which are supported by a previous pilot study using a propofol bolus dose, suggest that, compared to men, more rapid propofol metabolism may occur in women - a factor that may contribute to the mentioned differences in the efficacy of propofol anaesthesia between male and female patients.

  • 3. Haslemo, T
    et al.
    Loryan, Irena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Karolinska Institutet, Yerevan State Medical University.
    Ueda, N
    Mannheimer, B
    Bertilsson, L
    Ingelman-Sundberg, M
    Molden, E
    Eliasson, E
    UGT1A4*3 encodes significantly increased glucuronidation of olanzapine in patients on maintenance treatment and in recombinant systems2012In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 92, no 2, p. 221-227Article in journal (Refereed)
    Abstract [en]

    Olanzapine, a world leader in antipsychotic drugs, is used in the treatment of schizophrenia and bipolar disorder. There is considerable interpatient variability in its hepatic clearance. Polymorphic glucuronidation of olanzapine by uridine diphosphate glucuronosyltransferase 1A4 (UGT1A4) was investigated retrospectively in patient samples taken for routine therapeutic drug monitoring (TDM) and in recombinant metabolic systems in vitro. Multivariate analyses revealed that patients who were heterozygous as well as those who were homozygous for the UGT1A4*3 allelic variant had significantly higher concentrations of the major metabolite olanzapine 10-N-glucuronide in serum (+38% (P = 0.011) and +246% (P < 0.001), respectively). This finding was in line with the significant increases in glucuronidation activity of olanzapine observed with recombinant UGT1A4.3 (Val-48) as compared with UGT1A4.1 (Leu-48) (1.3-fold difference, P < 0.001). By contrast, serum concentrations of the parent drug were not significantly influenced by UGT1A4 genotype. Our findings therefore indicate that UGT1A4-mediated metabolism is not a major contributor to interpatient variability in olanzapine levels. However, with respect to other drugs for which UGT1A4 has a dominant role in clearance, increased glucuronidation encoded by UGT1A4*3 might impact the risk for subtherapeutic drug exposure.

  • 4.
    Loryan, Irena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Friden, Markus
    AstraZeneca Research and Development, Respiratory and Inflammatory Innovative Medicines, Department of Drug Metabolism and Pharmacokinetics, Mölndal, Swed.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The brain slice method for studying drug distribution in the CNS2013In: Fluids and Barriers of the CNS, ISSN 2045-8118, E-ISSN 2045-8118, Vol. 10, p. 6-Article in journal (Refereed)
    Abstract [en]

    The high-throughput brain slice method is a precise and robust technique for estimating the overall uptake of drugs into brain tissue through determination of the unbound volume of distribution in the brain (Vu,brain; ml·g brain-1). Vu,brain describes the relationship between the total drug concentration in the brain and the concentration of unbound drug in the brain interstitial fluid, regardless of blood–brain barrier function. The brain slice method is more physiologically based than the brain homogenate method with respect to the assessment of drug distribution in the brain because the cell-cell interactions, pH gradients and active transport systems are all conserved. The method provides information that is directly relevant to issues such as nonspecific binding to brain tissue, lysosomal trapping, and active uptake into the cells. For these reasons, the brain slice method is recommended for estimation of target-site pharmacokinetics in the early drug discovery process and fundamental pharmacological studies. This article provides a detailed protocol for the rat and mouse brain slice methods, with the aim of enabling simple, cost-effective profiling of compounds with diverse physicochemical properties. The procedure for assessing the viability of the brain slices after the 5 h incubation period is also described. The results are interpreted for a set of compounds covering a wide range of physicochemical properties and various pharmacological targets. Application of the method for evaluating the unbound intracellular-to-extracellular concentration ratio (Kp,uu,cell) and the unbound brain-to-plasma concentration ratio (Kp,uu,brain) is discussed.

  • 5.
    Loryan, Irena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hoppe, Edmund
    Grunenthal GmbH, D-52099 Aachen, Germany.
    Hansen, Klaus
    Grunenthal GmbH, D-52099 Aachen, Germany.
    Held, Felix
    Fraunhofer Chalmers Ctr, Chalmers Sci Pk, S-41288 Gothenburg, Sweden.; Chalmers Univ Technol, Dept Math Sci, S-41296 Gothenburg, Sweden.; Univ Gothenburg, S-41296 Gothenburg, Sweden.
    Kless, Achim
    Grunenthal GmbH, D-52099 Aachen, Germany.
    Linz, Klaus
    Grunenthal GmbH, D-52099 Aachen, Germany.
    Marossek, Virginia
    Grunenthal GmbH, D-52099 Aachen, Germany.; Bayer AG, Wuppertal, Germany.
    Nolte, Bert
    Grunenthal GmbH, D-52099 Aachen, Germany.; Peter Greven Physioderm GmbH, Euskirchen, Germany.
    Ratcliffe, Paul
    Grunenthal GmbH, D-52099 Aachen, Germany.
    Saunders, Derek
    Grunenthal GmbH, D-52099 Aachen, Germany.
    Terlinden, Rolf
    Grunenthal GmbH, D-52099 Aachen, Germany.
    Wegert, Anita
    Grunenthal GmbH, D-52099 Aachen, Germany.; Mercachem, Nijmegen, Netherlands.
    Welbers, André
    Grunenthal GmbH, D-52099 Aachen, Germany.
    Will, Olaf
    Grunenthal GmbH, D-52099 Aachen, Germany.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Quantitative Assessment of Drug Delivery to Tissues and Association with Phospholipidosis: A Case Study with Two Structurally Related Diamines in Development2017In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, no 12, p. 4362-4373Article in journal (Refereed)
    Abstract [en]

    Drug induced phospholipidosis (PLD) may be observed in the preclinical phase of drug development and pose strategic questions. As lysosomes have a central role in pathogenesis of PLD, assessment of lysosomal concentrations is important for understanding the pharmacokinetic basis of PLD manifestation and forecast of potential clinical appearance. Herein we present a systematic approach to provide insight into tissue-specific PLD by evaluation of unbound intracellular and lysosomal (reflecting acidic organelles) concentrations of two structurally related diprotic amines, GRT1 and GRT2. Their intratissue distribution was assessed using brain and lung slice assays. GRT1 induced PLD both in vitro and in vivo. GRT1 showed a high intracellular accumulation that was more pronounced in the lung, but did not cause cerebral PLD due to its effective efflux at the blood-brain barrier. Compared to GRT1, GRT2 revealed higher interstitial fluid concentrations in lung and brain, but more than 30-fold lower lysosomal trapping capacity. No signs of PLD were seen with GRT2. The different profile of GRT2 relative to GRT1 is due to a structural change resulting in a reduced basicity of one amino group. Hence, by distinct chemical modifications, undesired lysosomal trapping can be separated from desired drug delivery into different organs. In summary, assessment of intracellular unbound concentrations was instrumental in delineating the intercompound and intertissue differences in PLD induction in vivo and could be applied for identification of potential lysosomotropic compounds in drug development.

  • 6.
    Loryan, Irena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Karolinska Institutet, Yerevan State Medical University.
    Lindqvist, Marja
    Johansson, Inger
    Hiratsuka, Masahiro
    van der Heiden, Ilse
    van Schaik, Ron HN
    Jakobsson, Jan
    Ingelman-Sundberg, Magnus
    Influence of sex on propofol metabolism, a pilot study: implications for propofol anesthesia2012In: European Journal of Clinical Pharmacology, ISSN 0031-6970, Vol. 68, no 4, p. 397-406Article in journal (Refereed)
    Abstract [en]

    Purpose

    The basis of high intersubject variability of propofol metabolism is unclear. Therefore, we examined the influence of genetic polymorphisms of the key metabolizing enzymes cytochrome P450 2B6 (CYP2B6) and uridine diphosphate (UDP)-glucuronosyltransferase 1A9 (UGT1A9), age, and sex on propofol biotransformation in vitro and in vivo.

    Methods

    Plasma concentrations of propofol, 4-hydroxypropofol, and their glucuronides were measured over 20 min in 105 patients after a single intravenous bolus of propofol. Propofol 4-hydroxylation activity, genotypes, and content of CYP2B6 protein in 68 human livers were determined. The common single nucleotide polymorphisms (SNPs) for the CYP2B6 and UGT1A9 genes were analyzed by polymerase chain reaction (PCR).

    Results

    Plasma levels of propofol metabolites showed high interindividual variability (range of coefficient of variation 89–128%). This was supported by in vitro data showing similar variability of propofol 4-hydroxylation in liver microsomes and 1.9-fold higher CYP2B6 protein content in the livers from women. No significant relationships were revealed between the SNPs studied and propofol metabolism. However, patients’ sex had a pronounced effect on propofol metabolism. Thus, women had higher amounts of propofol glucuronide (1.25-fold; p = 0.03), 4-hydroxypropofol-1-glucuronide (2.1-fold; p = 0.0009), and 4-hydroxypropofol-4-glucuronide (1.7-fold; p  = 0.02) as shown by the weight-corrected area under the time–plasma concentration curve of metabolites. Additionally, the sexual dimorphism in 4-hydroxypropofol glucuronidation was prominent in the 35- to 64-year-old subgroup.

    Conclusions

    No significant effects of CYP2B6 and UGT1A9 SNPs or age on propofol metabolism were revealed in this pilot study, but there was a pronounced effect of sex, a finding that indicates an important factor for the previously described sex difference in systemic clearance of propofol seen.

  • 7.
    Loryan, Irena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Margareta, Hammarlund-Udenaes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Drug Discovery Methods for Studying Brain Drug Delivery and Distribution2014In: Drug Delivery to the Brain / [ed] Hammarlund-Udenaes Margareta; de Lange Elizabeth; Thorne Robert G., Springer, 2014Chapter in book (Refereed)
  • 8.
    Loryan, Irena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Melander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Svensson, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Payan, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    König, F.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jansson, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    In-depth neuropharmacokinetic analysis of antipsychotics based on a novel approach to estimate unbound target-site concentration in CNS regions: link to spatial receptor occupancy2016In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 21, no 11, p. 1527-1536Article in journal (Refereed)
    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.

  • 9.
    Loryan, Irena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sinha, Vikash
    Mackie, Claire
    van Peer, Achiel
    Drinkenburg, Wilhelmus
    Vermeulen, An
    Heald, Donald
    Margareta, Hammarlund-Udenaes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wassvik, Carola
    Molecular properties determining unbound intracellular and extracellular brain exposure of CNS drug candidates2015In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, p. 520-532Article in journal (Refereed)
    Abstract [en]

    In the present work we sought to gain a mechanistic understanding of the physicochemical properties that influence the transport of unbound drug across the blood-brain barrier (BBB) as well as the intra- and extracellular drug exposure in the brain. Interpretable molecular descriptors that significantly contribute to the three key neuropharmacokinetic properties related to BBB drug transport (Kp,uu,brain), intracellular accumulation (Kp,uu,cell) and binding and distribution in the brain (Vu,brain) for a set of 40 compounds were identified using partial least squares (PLS) analysis. The tailoring of drug properties for improved brain exposure includes decreasing the polarity and/or hydrogen bonding capacity. The design of CNS drug candidates with intracellular targets may benefit from an increase in basicity and/or the number of hydrogen bond donors. Applying this knowledge in drug discovery chemistry programs will allow designing compounds with more desirable CNS pharmacokinetic properties.

  • 10.
    Loryan, Irena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Vikash, Sinha
    Claire, Mackie
    Van Peer, Achiel
    Drinkenburg, Wilhelmus
    Vermeulen, An
    Morrison, Denise
    Monshouwer, Mario
    Heald, Donald
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mechanistic Understanding of Brain Drug Disposition to Optimize the Selection of Potential Neurotherapeutics in Drug Discovery2014In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 31, no 8, p. 2203-2219Article in journal (Refereed)
    Abstract [en]

    Purpose

    The current project was undertaken with the aim to propose and test an in-depth integrative analysis of neuropharmacokinetic (neuroPK) properties of new chemical entities (NCEs), thereby optimizing the routine of evaluation and selection of novel neurotherapeutics.

    Methods

    Forty compounds covering a wide range of physicochemical properties and various CNS targets were investigated. The combinatory mapping approach was used for the assessment of the extent of blood-brain and cellular barriers transport via estimation of unbound-compound brain (Kp,uu,brain) and cell (Kp,uu,cell) partitioning coefficients. Intra-brain distribution was evaluated using the brain slice method. Intra- and sub-cellular distribution was estimated via calculation of unbound-drug cytosolic and lysosomal partitioning coefficients.

    Results

    Assessment of Kp,uu,brain revealed extensive variability in the brain penetration properties across compounds, with a prevalence of compounds actively effluxed at the blood-brain barrier. Kp,uu,cell was valuable for identification of compounds with a tendency to accumulate intracellularly. Prediction of cytosolic and lysosomal partitioning provided insight into the subcellular accumulation. Integration of the neuroPK parameters with pharmacodynamic readouts demonstrated the value of the proposed approach in the evaluation of target engagement and NCE selection.

    Conclusions

    With the rather easily-performed combinatory mapping approach, it was possible to provide quantitative information supporting the decision making in the drug discovery setting.

  • 11. Yusof, Siti R
    et al.
    Mohd Uzid, Mahathir
    Teh, Eng-Huat
    Hanapi, Nur Aziah
    Mohideen, Mazlin
    Mohamad Arshad, Ahmad Saifuddin
    Mordi, Mohd Nizam
    Loryan, Irena
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Margareta, Hammarlund-Udenaes
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rate and extent of mitragynine and 7-hydroxymitragynine blood-brain barrier transport and their intra-brain distribution:: the missing link in pharmacodynamic studies2018In: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600Article in journal (Refereed)
    Abstract [en]

    Mitragyna speciosa is reported to be beneficial for the management of chronic pain and opioid withdrawal in the evolving opioid epidemic. Data on the blood-brain barrier (BBB) transport of mitragynine and 7-hydroxymitragynine, the active compounds of the plant, are still lacking and inconclusive. Here, we present for the first time the rate and the extent of mitragynine and 7-hydroxymitragynine transport across the BBB, with an investigation of their post-BBB intra-brain distribution. We utilized an in vitro BBB model to study the rate of BBB permeation of the compounds and their interaction with efflux transporter P-glycoprotein (P-gp). Mitragynine showed higher apical-to-basolateral (A-B, i.e. blood-to-brain side) permeability than 7-hydroxymitragynine. 7-Hydroxymitragynine showed a tendency to efflux, with efflux ratio (B-A/A-B) of 1.39. Both were found to inhibit the P-gp and are also subject to efflux by the P-gp. Assessment of the extent of BBB transport in vivo in rats from unbound brain to plasma concentration ratios (Kp,uu,brain ) revealed extensive efflux of both compounds, with less than 10 percent of unbound mitragynine and 7-hydroxymitragynine in plasma crossing the BBB. By contrast, the extent of intra-brain distribution was significantly different, with mitragynine having 18-fold higher brain tissue uptake in brain slice assay compared with 7-hydroxymitragynine. Mitragynine showed a moderate capacity to accumulate inside brain parenchymal cells, while 7-hydroxymitragynine showed restricted cellular barrier transport. The presented findings from this systematic investigation of brain pharmacokinetics of mitragynine and 7-hydroxymitragynine are essential for design and interpretation of in vivo experiments aiming to establish exposure-response relationship.

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