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  1. AU=Enoru Julius O.
  2. AU="Jin, Changfei"
  3. AU="Mantero, J"
  4. AU=Fekete Erzsbet AU=Fekete Erzsbet
  5. AU="Somasundaram, Kumaravel" AU="Somasundaram, Kumaravel"
  6. AU=Cui Huachun
  7. AU="Surgenor, Richard R"
  8. AU="Rowlands, Rachel"
  9. AU="Ferraz, Alexandre de Vicente"
  10. AU="Lee, Sang W."
  11. AU="Lingappa, Jairam"
  12. AU="Suo, Keke"
  13. AU=Tokonami Natsuko
  14. AU="Blevins, Hannah"
  15. AU="Sanders, Barton J."
  16. AU="Park, Hyun Ah"
  17. AU="Fields, Errol L"
  18. AU="Borisov, Alexander"
  19. AU="Ali, Ahmed E"
  20. AU="Carrasco Carrasco, E"
  21. AU="Massa, L"
  22. AU="Seki, Reiko"
  23. AU="Skowno, Justin"
  24. AU="Hikida, Hiroshi"
  25. AU="Wentzel, David C"
  26. AU="Priyadarshini, Subhadra"
  27. AU="Monemi, Sharareh"
  28. AU="Iannuzzi, Gregory"
  29. AU="Zhou, Ning"
  30. AU=Griffith A J
  31. AU="Schmidt-Pogoda, Antje"
  32. AU="A.Aich, "
  33. AU="Anding, Allyson L"

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  1. Artikel: Uptake Transporters at the Blood-Brain Barrier and Their Role in Brain Drug Disposition.

    Parvez, Md Masud / Sadighi, Armin / Ahn, Yeseul / Keller, Steve F / Enoru, Julius O

    Pharmaceutics

    2023  Band 15, Heft 10

    Abstract: Uptake drug transporters play a significant role in the pharmacokinetic of drugs within the brain, facilitating their entry into the central nervous system (CNS). Understanding brain drug disposition is always challenging, especially with respect to ... ...

    Abstract Uptake drug transporters play a significant role in the pharmacokinetic of drugs within the brain, facilitating their entry into the central nervous system (CNS). Understanding brain drug disposition is always challenging, especially with respect to preclinical to clinical translation. These transporters are members of the solute carrier (SLC) superfamily, which includes organic anion transporter polypeptides (OATPs), organic anion transporters (OATs), organic cation transporters (OCTs), and amino acid transporters. In this systematic review, we provide an overview of the current knowledge of uptake drug transporters in the brain and their contribution to drug disposition. Here, we also assemble currently available proteomics-based expression levels of uptake transporters in the human brain and their application in translational drug development. Proteomics data suggest that in association with efflux transporters, uptake drug transporters present at the BBB play a significant role in brain drug disposition. It is noteworthy that a significant level of species differences in uptake drug transporters activity exists, and this may contribute toward a disconnect in inter-species scaling. Taken together, uptake drug transporters at the BBB could play a significant role in pharmacokinetics (PK) and pharmacodynamics (PD). Continuous research is crucial for advancing our understanding of active uptake across the BBB.
    Sprache Englisch
    Erscheinungsdatum 2023-10-16
    Erscheinungsland Switzerland
    Dokumenttyp Journal Article ; Review
    ZDB-ID 2527217-2
    ISSN 1999-4923
    ISSN 1999-4923
    DOI 10.3390/pharmaceutics15102473
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Preclinical Metabolism, Pharmacokinetics and In Vivo Analysis of New Blood-Brain-Barrier Penetrant Fingolimod Analogues: FTY720-C2 and FTY720-Mitoxy.

    Enoru, Julius O / Yang, Barbara / Krishnamachari, Sesha / Villanueva, Ernesto / DeMaio, William / Watanyar, Adiba / Chinnasamy, Ramesh / Arterburn, Jeffrey B / Perez, Ruth G

    PloS one

    2016  Band 11, Heft 9, Seite(n) e0162162

    Abstract: Parkinson's disease (PD) is a neurodegenerative aging disorder in which postmortem PD brain exhibits neuroinflammation, as well as synucleinopathy-associated protein phosphatase 2A (PP2A) enzymatic activity loss. Based on our translational research, we ... ...

    Abstract Parkinson's disease (PD) is a neurodegenerative aging disorder in which postmortem PD brain exhibits neuroinflammation, as well as synucleinopathy-associated protein phosphatase 2A (PP2A) enzymatic activity loss. Based on our translational research, we began evaluating the PD-repurposing-potential of an anti-inflammatory, neuroprotective, and PP2A stimulatory oral drug that is FDA-approved for multiple sclerosis, FTY720 (fingolimod, Gilenya®). We also designed two new FTY720 analogues, FTY720-C2 and FTY720-Mitoxy, with modifications that affect drug potency and mitochondrial localization, respectively. Herein, we describe the metabolic stability and metabolic profiling of FTY720-C2 and FTY720-Mitoxy in liver microsomes and hepatocytes. Using mouse, rat, dog, monkey, and human liver microsomes the intrinsic clearance of FTY720-C2 was 22.5, 79.5, 6.0, 20.2 and 18.3 μL/min/mg; and for FTY720-Mitoxy was 1.8, 7.8, 1.4, 135.0 and 17.5 μL/min/mg, respectively. In hepatocytes, both FTY720-C2 and FTY720-Mitoxy were metabolized from the octyl side chain, generating a series of carboxylic acids similar to the parent FTY720, but without phosphorylated metabolites. To assess absorption and distribution, we gave equivalent single intravenous (IV) or oral doses of FTY720-C2 or FTY720-Mitoxy to C57BL/6 mice, with two mice per time point evaluated. After IV delivery, both FTY720-C2 and FTY720-Mitoxy were rapidly detected in plasma and brain; and reached peak concentrations at the first sampling time points. After oral dosing, FTY720-C2 was present in plasma and brain, although FTY720-Mitoxy was not orally bioavailable. Brain-to-plasma ratio of both compounds increased time-dependently, suggesting a preferential partitioning to the brain. PP2A activity in mouse adrenal gland increased ~2-fold after FTY720-C2 or FTY720-Mitoxy, as compared to untreated controls. In summary, FTY720-C2 and FTY720-Mitoxy both (i) crossed the blood-brain-barrier; (ii) produced metabolites similar to FTY720, except without phosphorylated species that cause S1P1-mediated-immunosuppression; and (iii) stimulated in vivo PP2A activity, all of which encourage additional preclinical assessment.
    Mesh-Begriff(e) Animals ; Blood-Brain Barrier/metabolism ; Fingolimod Hydrochloride/pharmacokinetics ; Hepatocytes/metabolism ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Microsomes, Liver/metabolism ; Protein Phosphatase 2/metabolism ; Rats
    Chemische Substanzen Protein Phosphatase 2 (EC 3.1.3.16) ; Fingolimod Hydrochloride (G926EC510T)
    Sprache Englisch
    Erscheinungsdatum 2016-09-09
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0162162
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: Preclinical Metabolism, Pharmacokinetics and In Vivo Analysis of New Blood-Brain-Barrier Penetrant Fingolimod Analogues

    Julius O Enoru / Barbara Yang / Sesha Krishnamachari / Ernesto Villanueva / William DeMaio / Adiba Watanyar / Ramesh Chinnasamy / Jeffrey B Arterburn / Ruth G Perez

    PLoS ONE, Vol 11, Iss 9, p e

    FTY720-C2 and FTY720-Mitoxy.

    2016  Band 0162162

    Abstract: Parkinson's disease (PD) is a neurodegenerative aging disorder in which postmortem PD brain exhibits neuroinflammation, as well as synucleinopathy-associated protein phosphatase 2A (PP2A) enzymatic activity loss. Based on our translational research, we ... ...

    Abstract Parkinson's disease (PD) is a neurodegenerative aging disorder in which postmortem PD brain exhibits neuroinflammation, as well as synucleinopathy-associated protein phosphatase 2A (PP2A) enzymatic activity loss. Based on our translational research, we began evaluating the PD-repurposing-potential of an anti-inflammatory, neuroprotective, and PP2A stimulatory oral drug that is FDA-approved for multiple sclerosis, FTY720 (fingolimod, Gilenya®). We also designed two new FTY720 analogues, FTY720-C2 and FTY720-Mitoxy, with modifications that affect drug potency and mitochondrial localization, respectively. Herein, we describe the metabolic stability and metabolic profiling of FTY720-C2 and FTY720-Mitoxy in liver microsomes and hepatocytes. Using mouse, rat, dog, monkey, and human liver microsomes the intrinsic clearance of FTY720-C2 was 22.5, 79.5, 6.0, 20.2 and 18.3 μL/min/mg; and for FTY720-Mitoxy was 1.8, 7.8, 1.4, 135.0 and 17.5 μL/min/mg, respectively. In hepatocytes, both FTY720-C2 and FTY720-Mitoxy were metabolized from the octyl side chain, generating a series of carboxylic acids similar to the parent FTY720, but without phosphorylated metabolites. To assess absorption and distribution, we gave equivalent single intravenous (IV) or oral doses of FTY720-C2 or FTY720-Mitoxy to C57BL/6 mice, with two mice per time point evaluated. After IV delivery, both FTY720-C2 and FTY720-Mitoxy were rapidly detected in plasma and brain; and reached peak concentrations at the first sampling time points. After oral dosing, FTY720-C2 was present in plasma and brain, although FTY720-Mitoxy was not orally bioavailable. Brain-to-plasma ratio of both compounds increased time-dependently, suggesting a preferential partitioning to the brain. PP2A activity in mouse adrenal gland increased ~2-fold after FTY720-C2 or FTY720-Mitoxy, as compared to untreated controls. In summary, FTY720-C2 and FTY720-Mitoxy both (i) crossed the blood-brain-barrier; (ii) produced metabolites similar to FTY720, except without phosphorylated species that cause S1P1-mediated-immunosuppression; and (iii) stimulated in vivo PP2A activity, all of which encourage additional preclinical assessment.
    Schlagwörter Medicine ; R ; Science ; Q
    Thema/Rubrik (Code) 610
    Sprache Englisch
    Erscheinungsdatum 2016-01-01T00:00:00Z
    Verlag Public Library of Science (PLoS)
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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