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Drug Distribution in Brain and Cerebrospinal Fluids in Relation to IC(50) Values in Aging and Alzheimer’s Disease, Using the Physiologically Based LeiCNS-PK3.0 Model

BACKGROUND: Very little knowledge exists on the impact of Alzheimer’s disease on the CNS target site pharmacokinetics (PK). AIM: To predict the CNS PK of cognitively healthy young and elderly and of Alzheimer’s patients using the physiologically based LeiCNS-PK3.0 model. METHODS: LeiCNS-PK3.0 was us...

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Autores principales: Saleh, Mohammed A. A., Bloemberg, Julia S., Elassaiss-Schaap, Jeroen, de Lange, Elizabeth C. M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9246802/
https://www.ncbi.nlm.nih.gov/pubmed/35606598
http://dx.doi.org/10.1007/s11095-022-03281-3
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author Saleh, Mohammed A. A.
Bloemberg, Julia S.
Elassaiss-Schaap, Jeroen
de Lange, Elizabeth C. M.
author_facet Saleh, Mohammed A. A.
Bloemberg, Julia S.
Elassaiss-Schaap, Jeroen
de Lange, Elizabeth C. M.
author_sort Saleh, Mohammed A. A.
collection PubMed
description BACKGROUND: Very little knowledge exists on the impact of Alzheimer’s disease on the CNS target site pharmacokinetics (PK). AIM: To predict the CNS PK of cognitively healthy young and elderly and of Alzheimer’s patients using the physiologically based LeiCNS-PK3.0 model. METHODS: LeiCNS-PK3.0 was used to predict the PK profiles in brain extracellular (brain(ECF)) and intracellular (brain(ICF)) fluids and cerebrospinal fluid of the subarachnoid space (CSF(SAS)) of donepezil, galantamine, memantine, rivastigmine, and semagacestat in young, elderly, and Alzheimer’s patients. The physiological parameters of LeiCNS-PK3.0 were adapted for aging and Alzheimer’s based on an extensive literature search. The CNS PK profiles at plateau for clinical dose regimens were related to in vitro IC(50) values of acetylcholinesterase, butyrylcholinesterase, N-methyl-D-aspartate, or gamma-secretase. RESULTS: The PK profiles of all drugs differed between the CNS compartments regarding plateau levels and fluctuation. Brain(ECF), brain(ICF) and CSF(SAS) PK profile relationships were different between the drugs. Aging and Alzheimer’s had little to no impact on CNS PK. Rivastigmine acetylcholinesterase IC(50) values were not reached. Semagacestat brain PK plateau levels were below the IC(50) of gamma-secretase for half of the interdose interval, unlike CSF(SAS) PK profiles that were consistently above IC(50.) CONCLUSION: This study provides insights into the relations between CNS compartments PK profiles, including target sites. CSF(SAS) PK appears to be an unreliable predictor of brain PK. Also, despite extensive changes in blood-brain barrier and brain properties in Alzheimer’s, this study shows that the impact of aging and Alzheimer’s pathology on CNS distribution of the five drugs is insignificant. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11095-022-03281-3.
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spelling pubmed-92468022022-07-02 Drug Distribution in Brain and Cerebrospinal Fluids in Relation to IC(50) Values in Aging and Alzheimer’s Disease, Using the Physiologically Based LeiCNS-PK3.0 Model Saleh, Mohammed A. A. Bloemberg, Julia S. Elassaiss-Schaap, Jeroen de Lange, Elizabeth C. M. Pharm Res Research Paper BACKGROUND: Very little knowledge exists on the impact of Alzheimer’s disease on the CNS target site pharmacokinetics (PK). AIM: To predict the CNS PK of cognitively healthy young and elderly and of Alzheimer’s patients using the physiologically based LeiCNS-PK3.0 model. METHODS: LeiCNS-PK3.0 was used to predict the PK profiles in brain extracellular (brain(ECF)) and intracellular (brain(ICF)) fluids and cerebrospinal fluid of the subarachnoid space (CSF(SAS)) of donepezil, galantamine, memantine, rivastigmine, and semagacestat in young, elderly, and Alzheimer’s patients. The physiological parameters of LeiCNS-PK3.0 were adapted for aging and Alzheimer’s based on an extensive literature search. The CNS PK profiles at plateau for clinical dose regimens were related to in vitro IC(50) values of acetylcholinesterase, butyrylcholinesterase, N-methyl-D-aspartate, or gamma-secretase. RESULTS: The PK profiles of all drugs differed between the CNS compartments regarding plateau levels and fluctuation. Brain(ECF), brain(ICF) and CSF(SAS) PK profile relationships were different between the drugs. Aging and Alzheimer’s had little to no impact on CNS PK. Rivastigmine acetylcholinesterase IC(50) values were not reached. Semagacestat brain PK plateau levels were below the IC(50) of gamma-secretase for half of the interdose interval, unlike CSF(SAS) PK profiles that were consistently above IC(50.) CONCLUSION: This study provides insights into the relations between CNS compartments PK profiles, including target sites. CSF(SAS) PK appears to be an unreliable predictor of brain PK. Also, despite extensive changes in blood-brain barrier and brain properties in Alzheimer’s, this study shows that the impact of aging and Alzheimer’s pathology on CNS distribution of the five drugs is insignificant. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11095-022-03281-3. Springer US 2022-05-23 2022 /pmc/articles/PMC9246802/ /pubmed/35606598 http://dx.doi.org/10.1007/s11095-022-03281-3 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Paper
Saleh, Mohammed A. A.
Bloemberg, Julia S.
Elassaiss-Schaap, Jeroen
de Lange, Elizabeth C. M.
Drug Distribution in Brain and Cerebrospinal Fluids in Relation to IC(50) Values in Aging and Alzheimer’s Disease, Using the Physiologically Based LeiCNS-PK3.0 Model
title Drug Distribution in Brain and Cerebrospinal Fluids in Relation to IC(50) Values in Aging and Alzheimer’s Disease, Using the Physiologically Based LeiCNS-PK3.0 Model
title_full Drug Distribution in Brain and Cerebrospinal Fluids in Relation to IC(50) Values in Aging and Alzheimer’s Disease, Using the Physiologically Based LeiCNS-PK3.0 Model
title_fullStr Drug Distribution in Brain and Cerebrospinal Fluids in Relation to IC(50) Values in Aging and Alzheimer’s Disease, Using the Physiologically Based LeiCNS-PK3.0 Model
title_full_unstemmed Drug Distribution in Brain and Cerebrospinal Fluids in Relation to IC(50) Values in Aging and Alzheimer’s Disease, Using the Physiologically Based LeiCNS-PK3.0 Model
title_short Drug Distribution in Brain and Cerebrospinal Fluids in Relation to IC(50) Values in Aging and Alzheimer’s Disease, Using the Physiologically Based LeiCNS-PK3.0 Model
title_sort drug distribution in brain and cerebrospinal fluids in relation to ic(50) values in aging and alzheimer’s disease, using the physiologically based leicns-pk3.0 model
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9246802/
https://www.ncbi.nlm.nih.gov/pubmed/35606598
http://dx.doi.org/10.1007/s11095-022-03281-3
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