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  • 1.
    Bjugård Nyberg, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Chen, Xiaomei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Donnelly, Mark
    Division of Quantitative Methods and Modelling, Office of Research and Standards, Office of Generic Drugs, Food and Drug Administration.
    Fang, Lanyan
    Division of Quantitative Methods and Modelling, Office of Research and Standards, Office of Generic Drugs, Food and Drug Administration.
    Zhao, Liang
    Division of Quantitative Methods and Modelling, Office of Research and Standards, Office of Generic Drugs, Food and Drug Administration.
    Karlsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hooker, Andrew
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Evaluation of model-integrated evidence approaches for pharmacokinetic bioequivalence studies using model averaging methodsManuscript (preprint) (Other academic)
  • 2.
    Chen, Xiaomei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bjugård Nyberg, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Donnelly, Mark
    Division of Quantitative Methods and Modelling, Office of Research and Standards, Office of Generic Drugs, Food and Drug Administration.
    Zhao, Liang
    Division of Quantitative Methods and Modelling, Office of Research and Standards, Office of Generic Drugs, Food and Drug Administration.
    Fang, Lanyan
    Division of Quantitative Methods and Modelling, Office of Research and Standards, Office of Generic Drugs, Food and Drug Administration.
    Karlsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hooker, Andrew
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Development and comparison of model-integrated evidence approaches for bioequivalence studies with pharmacokinetic endpointsManuscript (preprint) (Other academic)
  • 3.
    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.
    Maryam, Payan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Keep, Richard F
    University of Michigan, Ann Arbor, MI, USA.
    Smith, David E
    University of Michigan, Ann Arbor, MI, USA.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Effect of transporter inhibitioin on the distribution of cefadroxil in rat brain2014In: Fluids and Barriers of the CNS, E-ISSN 2045-8118, Vol. 11, no 25, p. 1-12Article in journal (Refereed)
    Download full text (pdf)
    Chen et al 2014
  • 4.
    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, 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.

    Download full text (pdf)
    fulltext
  • 5.
    Chen, Xiaomei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, 428 Church St, Ann Arbor, MI 48109 USA..
    Slättengren, Tim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    de Lange, Elizabeth C. M.
    Leiden Acad Ctr Drug Res, Dept Pharmacol, Leiden, Netherlands..
    Smith, David E.
    Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, 428 Church St, Ann Arbor, MI 48109 USA..
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Revisiting atenolol as a low passive permeability marker2017In: Fluids and Barriers of the CNS, E-ISSN 2045-8118, Vol. 14, article id 30Article in journal (Refereed)
    Abstract [en]

    Background: Atenolol, a hydrophilic beta blocker, has been used as a model drug for studying passive permeability of biological membranes such as the blood-brain barrier (BBB) and the intestinal epithelium. However, the extent of S-atenolol (the active enantiomer) distribution in brain has never been evaluated, at equilibrium, to confirm that no transporters are involved in its transport at the BBB.

    Methods: To assess whether S-atenolol, in fact, depicts the characteristics of a low passive permeable drug at the BBB, a microdialysis study was performed in rats to monitor the unbound concentrations of S-atenolol in brain extracellular fluid (ECF) and plasma during and after intravenous infusion. A pharmacokinetic model was developed, based on the microdialysis data, to estimate the permeability clearance of S-atenolol into and out of brain. In addition, the nonspecific binding of S-atenolol in brain homogenate was evaluated using equilibrium dialysis.

    Results: The steady-state ratio of unbound S-atenolol concentrations in brain ECF to that in plasma (i.e., -K-p,K-uu,K-brain) was 3.5% +/- 0.4%, a value much less than unity. The unbound volume of distribution in brain -(V-u,V- brain) of S-atenolol was also calculated as 0.69 +/- 0.10 mL/g brain, indicating that S-atenolol is evenly distributed within brain parenchyma. Lastly, equilibrium dialysis showed limited nonspecific binding of S-atenolol in brain homogenate with an unbound fraction -(f(u, brain)) of 0.88 +/- 0.07.

    Conclusions: It is concluded, based on -K-p,K-uu,K-brain being much smaller than unity, that S-atenolol is actively effluxed at the BBB, indicating the need to re-consider S-atenolol as a model drug for passive permeability studies of BBB transport or intestinal absorption.

    Download full text (pdf)
    fulltext
  • 6.
    Sharan, Satish
    et al.
    US FDA, DQMM, ORS, OGD, CDER, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA.
    Fang, Lanyan
    US FDA, DQMM, ORS, OGD, CDER, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA.
    Lukacova, Viera
    Simulat Plus Inc, Simulat Sci, Lancaster, CA USA.
    Chen, Xiaomei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hooker, Andrew C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Model-Informed Drug Development for Long-Acting Injectable Products: Summary of American College of Clinical Pharmacology Symposium2021In: Clinical Pharmacology in Drug Development, ISSN 2160-763X, E-ISSN 2160-7648, Vol. 10, no 3, p. 220-228Article in journal (Other academic)
1 - 6 of 6
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