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Publications (6 of 6) Show all publications
Sharan, S., Fang, L., Lukacova, V., Chen, X., Hooker, A. C. & Karlsson, M. O. (2021). Model-Informed Drug Development for Long-Acting Injectable Products: Summary of American College of Clinical Pharmacology Symposium. Clinical Pharmacology in Drug Development, 10(3), 220-228
Open this publication in new window or tab >>Model-Informed Drug Development for Long-Acting Injectable Products: Summary of American College of Clinical Pharmacology Symposium
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2021 (English)In: Clinical Pharmacology in Drug Development, ISSN 2160-763X, E-ISSN 2160-7648, Vol. 10, no 3, p. 220-228Article in journal, Editorial material (Other academic) Published
Place, publisher, year, edition, pages
The American College of Clinical PharmacologyThe American College of Clinical Pharmacology, 2021
Keywords
MIDD, Model-Informed Drug Development, LAI, Long Acting Injectable, PBPK, Quantitative Clinical Pharmacology, QCP, Generic Drug, Bioequivalence, Modeling and Simulation
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-438799 (URN)10.1002/cpdd.928 (DOI)000620815300001 ()33624456 (PubMedID)
Available from: 2021-03-30 Created: 2021-03-30 Last updated: 2024-01-15Bibliographically approved
Chen, X., Slättengren, T., de Lange, E. C. M., Smith, D. E. & Hammarlund-Udenaes, M. (2017). Revisiting atenolol as a low passive permeability marker. Fluids and Barriers of the CNS, 14, Article ID 30.
Open this publication in new window or tab >>Revisiting atenolol as a low passive permeability marker
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2017 (English)In: Fluids and Barriers of the CNS, E-ISSN 2045-8118, Vol. 14, article id 30Article in journal (Refereed) Published
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.

Keywords
Atenolol, Blood-brain barrier, Microdialysis, Unbound equilibrium partition coefficient (K-p, K-uu, K-brain), Unbound volume of distribution in brain (V-u, V-brain), Passive permeability, Transporters, Pharmacokinetics, Lipophilicity
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-341367 (URN)10.1186/s12987-017-0078-x (DOI)000414175000001 ()29089037 (PubMedID)
Available from: 2018-02-08 Created: 2018-02-08 Last updated: 2024-01-17Bibliographically approved
Chen, X., Loryan, I., Maryam, P., Keep, R. F., Smith, D. E. & Hammarlund-Udenaes, M. (2014). Effect of transporter inhibitioin on the distribution of cefadroxil in rat brain. Fluids and Barriers of the CNS, 11(25), 1-12
Open this publication in new window or tab >>Effect of transporter inhibitioin on the distribution of cefadroxil in rat brain
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2014 (English)In: Fluids and Barriers of the CNS, E-ISSN 2045-8118, Vol. 11, no 25, p. 1-12Article in journal (Refereed) Published
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-236367 (URN)10.1186/2045-8118-11-25 (DOI)
Available from: 2014-11-18 Created: 2014-11-18 Last updated: 2024-01-17Bibliographically approved
Chen, X., Loryan, I., Payan, M., Keep, R., Smith, D. E. & Margareta, H.-U. (2014). Effect of transporter inhibition on the distribution of cefadroxil in rat brain. Fluids and Barriers of the CNS, 11, Article ID 25.
Open this publication in new window or tab >>Effect of transporter inhibition on the distribution of cefadroxil in rat brain
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2014 (English)In: Fluids and Barriers of the CNS, E-ISSN 2045-8118, Vol. 11, article id 25Article in journal (Refereed) Published
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.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-236220 (URN)10.1186/2045-8118-11-25 (DOI)
Available from: 2014-11-15 Created: 2014-11-15 Last updated: 2024-01-17Bibliographically approved
Chen, X., Bjugård Nyberg, H., Donnelly, M., Zhao, L., Fang, L., Karlsson, M. & Hooker, A.Development and comparison of model-integrated evidence approaches for bioequivalence studies with pharmacokinetic endpoints.
Open this publication in new window or tab >>Development and comparison of model-integrated evidence approaches for bioequivalence studies with pharmacokinetic endpoints
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(English)Manuscript (preprint) (Other academic)
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-517824 (URN)
Available from: 2023-12-13 Created: 2023-12-13 Last updated: 2023-12-17
Bjugård Nyberg, H., Chen, X., Donnelly, M., Fang, L., Zhao, L., Karlsson, M. & Hooker, A.Evaluation of model-integrated evidence approaches for pharmacokinetic bioequivalence studies using model averaging methods.
Open this publication in new window or tab >>Evaluation of model-integrated evidence approaches for pharmacokinetic bioequivalence studies using model averaging methods
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(English)Manuscript (preprint) (Other academic)
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-517823 (URN)
Available from: 2023-12-13 Created: 2023-12-13 Last updated: 2023-12-17
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0009-0002-0663-0532

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