Pharmacokinetics of Novel Dopamine Transporter Inhibitor CE-123 and Modafinil with a Focus on Central Nervous System Distribution
<i>S</i>-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 <i>S...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/23/16956 |
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| author | Iva Spreitzer Josefin Keife Tobias Strasser Predrag Kalaba Jana Lubec Winfried Neuhaus Gert Lubec Thierry Langer Judith Wackerlig Irena Loryan |
| author_facet | Iva Spreitzer Josefin Keife Tobias Strasser Predrag Kalaba Jana Lubec Winfried Neuhaus Gert Lubec Thierry Langer Judith Wackerlig Irena Loryan |
| author_sort | Iva Spreitzer |
| collection | DOAJ |
| description | <i>S</i>-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 <i>S</i>-CE-123 and <i>R</i>-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, <i>S</i>-CE-123 demonstrates a significantly superior extent of transport across the blood–brain barrier (BBB), with an unbound brain-to-plasma concentration ratio (K<sub>p,uu,brain</sub>) of 0.5, compared to <i>R</i>-modafinil’s K<sub>p,uu,brain</sub> 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 <i>S</i>-CE-123 primarily localizes in the brain interstitial space, whereas <i>R</i>-modafinil distributes more evenly across both sides of the plasma membrane of the brain’s parenchymal cells (K<sub>p,uu,cell</sub>). Furthermore, our study highlights the substantial differences in hepatic metabolic stability, with <i>S</i>-CE-123 having a 9.3-fold faster metabolism compared to <i>R</i>-modafinil. In summary, the combination of improved BBB transport and higher affinity of <i>S</i>-CE-123 to dopamine transporters in comparison to <i>R</i>-modafinil makes <i>S</i>-CE-123 a promising candidate for further testing for the treatment of cognitive decline. |
| first_indexed | 2024-03-09T01:49:50Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T01:49:50Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-625f0373666f4c3db661f5ba229d286d2023-12-08T15:17:51ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-11-0124231695610.3390/ijms242316956Pharmacokinetics of Novel Dopamine Transporter Inhibitor CE-123 and Modafinil with a Focus on Central Nervous System DistributionIva Spreitzer0Josefin Keife1Tobias Strasser2Predrag Kalaba3Jana Lubec4Winfried Neuhaus5Gert Lubec6Thierry Langer7Judith Wackerlig8Irena Loryan9Department of Pharmaceutical Sciences, University of Vienna, 1090 Vienna, AustriaTranslational Pharmacokinetics/Pharmacodynamics Group, Department of Pharmacy, Uppsala University, 75123 Uppsala, SwedenDepartment of Pharmaceutical Sciences, University of Vienna, 1090 Vienna, AustriaDepartment of Pharmaceutical Sciences, University of Vienna, 1090 Vienna, AustriaProgramme for Proteomics, Paracelsus Medical University, 5020 Salzburg, AustriaCompetence Unit Molecular Diagnostics, Center Health and Bioresources, AIT Austrian Institute of Technology GmbH, 1210 Vienna, AustriaProgramme for Proteomics, Paracelsus Medical University, 5020 Salzburg, AustriaDepartment of Pharmaceutical Sciences, University of Vienna, 1090 Vienna, AustriaDepartment of Pharmaceutical Sciences, University of Vienna, 1090 Vienna, AustriaTranslational Pharmacokinetics/Pharmacodynamics Group, Department of Pharmacy, Uppsala University, 75123 Uppsala, Sweden<i>S</i>-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 <i>S</i>-CE-123 and <i>R</i>-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, <i>S</i>-CE-123 demonstrates a significantly superior extent of transport across the blood–brain barrier (BBB), with an unbound brain-to-plasma concentration ratio (K<sub>p,uu,brain</sub>) of 0.5, compared to <i>R</i>-modafinil’s K<sub>p,uu,brain</sub> 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 <i>S</i>-CE-123 primarily localizes in the brain interstitial space, whereas <i>R</i>-modafinil distributes more evenly across both sides of the plasma membrane of the brain’s parenchymal cells (K<sub>p,uu,cell</sub>). Furthermore, our study highlights the substantial differences in hepatic metabolic stability, with <i>S</i>-CE-123 having a 9.3-fold faster metabolism compared to <i>R</i>-modafinil. In summary, the combination of improved BBB transport and higher affinity of <i>S</i>-CE-123 to dopamine transporters in comparison to <i>R</i>-modafinil makes <i>S</i>-CE-123 a promising candidate for further testing for the treatment of cognitive decline.https://www.mdpi.com/1422-0067/24/23/16956dopamine transporter inhibitor<i>S</i>-CE-123<i>R</i>-modafinilneuropharmacokinetictissue distributionmetabolism |
| spellingShingle | Iva Spreitzer Josefin Keife Tobias Strasser Predrag Kalaba Jana Lubec Winfried Neuhaus Gert Lubec Thierry Langer Judith Wackerlig Irena Loryan Pharmacokinetics of Novel Dopamine Transporter Inhibitor CE-123 and Modafinil with a Focus on Central Nervous System Distribution International Journal of Molecular Sciences dopamine transporter inhibitor <i>S</i>-CE-123 <i>R</i>-modafinil neuropharmacokinetic tissue distribution metabolism |
| title | Pharmacokinetics of Novel Dopamine Transporter Inhibitor CE-123 and Modafinil with a Focus on Central Nervous System Distribution |
| title_full | Pharmacokinetics of Novel Dopamine Transporter Inhibitor CE-123 and Modafinil with a Focus on Central Nervous System Distribution |
| title_fullStr | Pharmacokinetics of Novel Dopamine Transporter Inhibitor CE-123 and Modafinil with a Focus on Central Nervous System Distribution |
| title_full_unstemmed | Pharmacokinetics of Novel Dopamine Transporter Inhibitor CE-123 and Modafinil with a Focus on Central Nervous System Distribution |
| title_short | Pharmacokinetics of Novel Dopamine Transporter Inhibitor CE-123 and Modafinil with a Focus on Central Nervous System Distribution |
| title_sort | pharmacokinetics of novel dopamine transporter inhibitor ce 123 and modafinil with a focus on central nervous system distribution |
| topic | dopamine transporter inhibitor <i>S</i>-CE-123 <i>R</i>-modafinil neuropharmacokinetic tissue distribution metabolism |
| url | https://www.mdpi.com/1422-0067/24/23/16956 |
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