Revisiting Cerebrospinal Fluid Flow Direction and Rate in Physiologically Based Pharmacokinetic Model
The bidirectional pulsatile movement of cerebrospinal fluid (CSF), instead of the traditionally believed unidirectional and constant CSF circulation, has been demonstrated. In the present study, the structure and parameters of the CSF compartments were revisited in our comprehensive and validated ce...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-08-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/9/1764 |
| _version_ | 1797483668831207424 |
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| author | Makoto Hirasawa Elizabeth C. M. de Lange |
| author_facet | Makoto Hirasawa Elizabeth C. M. de Lange |
| author_sort | Makoto Hirasawa |
| collection | DOAJ |
| description | The bidirectional pulsatile movement of cerebrospinal fluid (CSF), instead of the traditionally believed unidirectional and constant CSF circulation, has been demonstrated. In the present study, the structure and parameters of the CSF compartments were revisited in our comprehensive and validated central nervous system (CNS)-specific, physiologically based pharmacokinetic (PBPK) model of healthy rats (LeiCNS-PK3.0). The bidirectional and site-dependent CSF movement was incorporated into LeiCNS-PK3.0 to create the new LeiCNS-PK“3.1” model. The physiological CSF movement rates in healthy rats that are unavailable from the literature were estimated by fitting the PK data of sucrose, a CSF flow marker, after intra-CSF administration. The capability of LeiCNS-PK3.1 to describe the PK profiles of other molecules was compared with that of the original LeiCNS-PK3.0 model. LeiCNS-PK3.1 demonstrated superior description of the CSF PK profiles of a range of small molecules after intra-CSF administration over LeiCNS-PK3.0. LeiCNS-PK3.1 also retained the same level of predictability of CSF PK profiles in cisterna magna after intravenous administration. These results support the theory of bidirectional and site-dependent CSF movement across the entire CSF space over unidirectional and constant CSF circulation in healthy rats, pointing out the need to revisit the structures and parameters of CSF compartments in CNS-PBPK models. |
| first_indexed | 2024-03-09T22:51:18Z |
| format | Article |
| id | doaj.art-6322cb82e42441bb9ce9a278b8f1cf65 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T22:51:18Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-6322cb82e42441bb9ce9a278b8f1cf652023-11-23T18:20:03ZengMDPI AGPharmaceutics1999-49232022-08-01149176410.3390/pharmaceutics14091764Revisiting Cerebrospinal Fluid Flow Direction and Rate in Physiologically Based Pharmacokinetic ModelMakoto Hirasawa0Elizabeth C. M. de Lange1Division of Systems Pharmacology and Pharmacy, Leiden Academic Center for Drug Research, Leiden University, 2333 CC Leiden, The NetherlandsDivision of Systems Pharmacology and Pharmacy, Leiden Academic Center for Drug Research, Leiden University, 2333 CC Leiden, The NetherlandsThe bidirectional pulsatile movement of cerebrospinal fluid (CSF), instead of the traditionally believed unidirectional and constant CSF circulation, has been demonstrated. In the present study, the structure and parameters of the CSF compartments were revisited in our comprehensive and validated central nervous system (CNS)-specific, physiologically based pharmacokinetic (PBPK) model of healthy rats (LeiCNS-PK3.0). The bidirectional and site-dependent CSF movement was incorporated into LeiCNS-PK3.0 to create the new LeiCNS-PK“3.1” model. The physiological CSF movement rates in healthy rats that are unavailable from the literature were estimated by fitting the PK data of sucrose, a CSF flow marker, after intra-CSF administration. The capability of LeiCNS-PK3.1 to describe the PK profiles of other molecules was compared with that of the original LeiCNS-PK3.0 model. LeiCNS-PK3.1 demonstrated superior description of the CSF PK profiles of a range of small molecules after intra-CSF administration over LeiCNS-PK3.0. LeiCNS-PK3.1 also retained the same level of predictability of CSF PK profiles in cisterna magna after intravenous administration. These results support the theory of bidirectional and site-dependent CSF movement across the entire CSF space over unidirectional and constant CSF circulation in healthy rats, pointing out the need to revisit the structures and parameters of CSF compartments in CNS-PBPK models.https://www.mdpi.com/1999-4923/14/9/1764cerebrospinal fluidCSFCSF physiologybidirectional pulsatile CSF movementintra-CSF administrationphysiologically based pharmacokinetic model |
| spellingShingle | Makoto Hirasawa Elizabeth C. M. de Lange Revisiting Cerebrospinal Fluid Flow Direction and Rate in Physiologically Based Pharmacokinetic Model Pharmaceutics cerebrospinal fluid CSF CSF physiology bidirectional pulsatile CSF movement intra-CSF administration physiologically based pharmacokinetic model |
| title | Revisiting Cerebrospinal Fluid Flow Direction and Rate in Physiologically Based Pharmacokinetic Model |
| title_full | Revisiting Cerebrospinal Fluid Flow Direction and Rate in Physiologically Based Pharmacokinetic Model |
| title_fullStr | Revisiting Cerebrospinal Fluid Flow Direction and Rate in Physiologically Based Pharmacokinetic Model |
| title_full_unstemmed | Revisiting Cerebrospinal Fluid Flow Direction and Rate in Physiologically Based Pharmacokinetic Model |
| title_short | Revisiting Cerebrospinal Fluid Flow Direction and Rate in Physiologically Based Pharmacokinetic Model |
| title_sort | revisiting cerebrospinal fluid flow direction and rate in physiologically based pharmacokinetic model |
| topic | cerebrospinal fluid CSF CSF physiology bidirectional pulsatile CSF movement intra-CSF administration physiologically based pharmacokinetic model |
| url | https://www.mdpi.com/1999-4923/14/9/1764 |
| work_keys_str_mv | AT makotohirasawa revisitingcerebrospinalfluidflowdirectionandrateinphysiologicallybasedpharmacokineticmodel AT elizabethcmdelange revisitingcerebrospinalfluidflowdirectionandrateinphysiologicallybasedpharmacokineticmodel |