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- Spreitzer, Iva, et al.
(författare)
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Pharmacokinetics of Novel Dopamine Transporter Inhibitor CE-123 and Modafinil with a Focus on Central Nervous System Distribution
- 2023
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 24:23
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Tidskriftsartikel (refereegranskat)abstract
- 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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