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Pharmacokinetics of...
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Spreitzer, IvaUniv Vienna, Dept Pharmaceut Sci, A-1090 Vienna, Austria.;Univ Vienna, Vienna Doctoral Sch Pharmaceut Nutr & Sport Sci, A-1090 Vienna, Austria.
(författare)
Pharmacokinetics of Novel Dopamine Transporter Inhibitor CE-123 and Modafinil with a Focus on Central Nervous System Distribution
- Artikel/kapitelEngelska2023
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MDPI,2023
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electronicrdacarrier
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LIBRIS-ID:oai:DiVA.org:uu-518759
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-518759URI
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https://doi.org/10.3390/ijms242316956DOI
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Språk:engelska
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Sammanfattning på:engelska
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S-CE-123, a novel dopamine transporter inhibitor, has emerged as a potential candidate for cognitive enhancement. The objective of this study was to compare the tissue distribution profiles, with a specific focus on central nervous system distribution and metabolism, of S-CE-123 and R-modafinil. To address this objective, a precise liquid chromatography-high resolution mass spectrometry method was developed and partially validated. Neuropharmacokinetic parameters were assessed using the Combinatory Mapping Approach. Our findings reveal distinct differences between the two compounds. Notably, S-CE-123 demonstrates a significantly superior extent of transport across the blood-brain barrier (BBB), with an unbound brain-to-plasma concentration ratio (K-p,K-uu,K-brain) of 0.5, compared to R-modafinil's K-p,K-uu,K-brain of 0.1. A similar pattern was observed for the transport across the blood-spinal cord barrier. Concerning the drug transport across cellular membranes, we observed that S-CE-123 primarily localizes in the brain interstitial space, whereas R-modafinil distributes more evenly across both sides of the plasma membrane of the brain's parenchymal cells (K-p,K-uu,K-cell). Furthermore, our study highlights the substantial differences in hepatic metabolic stability, with S-CE-123 having a 9.3-fold faster metabolism compared to R-modafinil. In summary, the combination of improved BBB transport and higher affinity of S-CE-123 to dopamine transporters in comparison to R-modafinil makes S-CE-123 a promising candidate for further testing for the treatment of cognitive decline.
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Keife, JosefinUppsala universitet,Institutionen för farmaci
(författare)
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Strasser, TobiasUniv Vienna, Dept Pharmaceut Sci, A-1090 Vienna, Austria.
(författare)
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Kalaba, PredragUniv Vienna, Dept Pharmaceut Sci, A-1090 Vienna, Austria.
(författare)
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Lubec, JanaParacelsus Med Univ, Programme Prote, A-5020 Salzburg, Austria.
(författare)
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Neuhaus, WinfriedAIT Austrian Inst Technol GmbH, Ctr Hlth & Bioresources, Competence Unit Mol Diagnost, A-1210 Vienna, Austria.;Danube Private Univ, Fac Med & Dent, Dept Med, A-3500 Krems, Austria.
(författare)
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Lubec, GertParacelsus Med Univ, Programme Prote, A-5020 Salzburg, Austria.
(författare)
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Langer, ThierryUniv Vienna, Dept Pharmaceut Sci, A-1090 Vienna, Austria.
(författare)
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Wackerlig, JudithUniv Vienna, Dept Pharmaceut Sci, A-1090 Vienna, Austria.
(författare)
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Loryan, Irena,Associate Professor (Docent),1977-Uppsala universitet,Institutionen för farmaci(Swepub:uu)irelo664
(författare)
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Univ Vienna, Dept Pharmaceut Sci, A-1090 Vienna, Austria.;Univ Vienna, Vienna Doctoral Sch Pharmaceut Nutr & Sport Sci, A-1090 Vienna, Austria.Institutionen för farmaci
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:International Journal of Molecular Sciences: MDPI24:231661-65961422-0067
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Spreitzer, Iva
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Keife, Josefin
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Strasser, Tobias
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Kalaba, Predrag
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Lubec, Jana
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Neuhaus, Winfrie ...
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Lubec, Gert
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Langer, Thierry
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Wackerlig, Judit ...
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Loryan, Irena, A ...
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