ArticleJournal of pharmacokinetics and pharmacodynamics2013
The impact of P-gp functionality on non-steady state relationships between CSF and brain extracellular fluid.
Article in Journal of pharmacokinetics and pharmacodynamics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
25 citing papers in PubMed, 49 citations in OpenAlex.
- Intranasal drug delivery to the brain for neurodegenerative diseases: Current efforts and challenges in delivery platforms and modeling.Advanced drug delivery reviews · 2026Review
- In Vivo Electrochemical Monitoring of Safinamide Pharmacokinetics in the Brain Explores Its Correlation With Vision-Related Neuronal Activity.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Reliability of in vitro data for the mechanistic prediction of brain extracellular fluid pharmacokinetics of P-glycoprotein substrates in vivo; are we scaling correctly?Journal of pharmacokinetics and pharmacodynamics · 2025Article
- Cerebral Ischemia Protection After Aneurysmal Subarachnoid Hemorrhage: CSF Nimodipine Levels After Intravenous Versus Oral Nimodipine Administration.Clinical pharmacology and therapeutics · 2025Article
- Role of Tissue Hydraulic Permeability in Convection-Enhanced Delivery of Nanoparticle-Encapsulated Chemotherapy Drugs to Brain Tumour.Pharmaceutical research · 2022Article
- In Vitro to In Vivo Extrapolation Linked to Physiologically Based Pharmacokinetic Models for Assessing the Brain Drug Disposition.The AAPS journal · 2022Review
- Understanding Drug Delivery to the Brain Using Liposome-Based Strategies: Studies that Provide Mechanistic Insights Are Essential.The AAPS journal · 2021Review
- Modeling the Effect of Binding Kinetics in Spatial Drug Distribution in the Brain.Computational and mathematical methods in medicine · 2021Article
- Improving the Prediction of Local Drug Distribution Profiles in the Brain with a New 2D Mathematical Model.Bulletin of mathematical biology · 2019Article
- Mind the Gaps: Ontogeny of Human Brain P-gp and Its Impact on Drug Toxicity.The AAPS journal · 2019Review
- The need for mathematical modelling of spatial drug distribution within the brain.Fluids and barriers of the CNS · 2019Review
- Clinical Pharmacokinetics and Pharmacodynamics of Drugs in the Central Nervous System.Clinical pharmacokinetics · 2018Review
- Barriers to Effective Drug Treatment for Brain Metastases: A Multifactorial Problem in the Delivery of Precision Medicine.Pharmaceutical research · 2018Review
- Predicting Drug Concentration-Time Profiles in Multiple CNS Compartments Using a Comprehensive Physiologically-Based Pharmacokinetic Model.CPT: pharmacometrics & systems pharmacology · 2017Article
- Microdialysis as an Important Technique in Systems Pharmacology-a Historical and Methodological Review.The AAPS journal · 2017Review
- Microdialysis: the Key to Physiologically Based Model Prediction of Human CNS Target Site Concentrations.The AAPS journal · 2017Review
- Importance of Drug Pharmacokinetics at the Site of Action.Clinical and translational science · 2017Review
- A Generic Multi-Compartmental CNS Distribution Model Structure for 9 Drugs Allows Prediction of Human Brain Target Site Concentrations.Pharmaceutical research · 2017Article
- A four-compartment PBPK heart model accounting for cardiac metabolism - model development and application.Scientific reports · 2017Article
- Reliability of In Vitro and In Vivo Methods for Predicting the Effect of P-Glycoprotein on the Delivery of Antidepressants to the Brain.Clinical pharmacokinetics · 2016Review
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In the development of central nervous system (CNS)-targeted drugs, the prediction of human CNS target exposure is a big challenge. Cerebrospinal fluid (CSF) concentrations have often been suggested as a 'good enough' surrogate for brain extracellular fluid (brainECF, brain target site) concentrations in humans. However, brain anatomy and physiology indicates prudence. We have applied a multiple microdialysis probe approach in rats, for continuous measurement and direct comparison of quinidine kinetics in brainECF, CSF, and plasma. The data obtained indicated important differences between brainECF and CSF kinetics, with brainECF kinetics being most sensitive to P-gp inhibition. To describe the data we developed a systems-based pharmacokinetic model. Our findings indicated that: (1) brainECF- and CSF-to-unbound plasma AUC0-360 ratios were all over 100 %; (2) P-gp also restricts brain intracellular exposure; (3) a direct transport route of quinidine from plasma to brain cells exists; (4) P-gp-mediated efflux of quinidine at the blood-brain barrier seems to result of combined efflux enhancement and influx hindrance; (5) P-gp at the blood-CSF barrier either functions as an efflux transporter or is not functioning at all. It is concluded that in parallel obtained data on unbound brainECF, CSF and plasma concentrations, under dynamic conditions, is a complex but most valid approach to reveal the mechanisms underlying the relationship between brainECF and CSF concentrations. This relationship is significantly influenced by activity of P-gp. Therefore, information on functionality of P-gp is required for the prediction of human brain target site concentrations of P-gp substrates on the basis of human CSF concentrations.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.