Impact of CNS Diseases on Drug Delivery to Brain Extracellular and Intracellular Target Sites in Human: A "WHAT-IF" Simulation Study.

Mohammed A A Saleh,Elizabeth C M De Lange

doi:10.3390/pharmaceutics13010095

Mohammed A A Saleh, Elizabeth C M De Lange

Open Access

https://doi.org/10.3390/pharmaceutics13010095

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Journal: Pharmaceutics	Publication Date: Jan 13, 2021
Citations: 13	License type: CC BY 4.0

Affiliation: Centre for Human Drug Research, Leiden University

Abstract

The blood–brain barrier (BBB) is equipped with unique physical and functional processes that control central nervous system (CNS) drug transport and the resulting concentration–time profiles (PK). In CNS diseases, the altered BBB and CNS pathophysiology may affect the CNS PK at the drug target sites in the brain extracellular fluid (brainECF) and intracellular fluid (brainICF) that may result in changes in CNS drug effects. Here, we used our human CNS physiologically-based PK model (LeiCNS-PK3.0) to investigate the impact of altered cerebral blood flow (CBF), tight junction paracellular pore radius (pararadius), brainECF volume, and pH of brainECF (pHECF) and of brainICF (pHICF) on brainECF and brainICF PK for 46 small drugs with distinct physicochemical properties. LeiCNS-PK3.0 simulations showed a drug-dependent effect of the pathophysiological changes on the rate and extent of BBB transport and on brainECF and brainICF PK. Altered pararadius, pHECF, and pHICF affected both the rate and extent of BBB drug transport, whereas changes in CBF and brainECF volume modestly affected the rate of BBB drug transport. While the focus is often on BBB paracellular and active transport processes, this study indicates that also changes in pH should be considered for their important implications on brainECF and brainICF target site PK.

Highlights

Both the rate and extent of central nervous system (CNS) unbound drug transport determine CNS concentration–time profiles of the unbound drug (PK) [1]
LeiCNS-PK3.0 simulations showed a drug-dependent effect of the pathophysiological changes on the rate and extent of blood–brain barrier (BBB) transport and on brainECF and brainICF PK
Altered pararadius, pH of brainECF (pHECF), and pHICF affected both the rate and extent of BBB drug transport, whereas changes in cerebral blood flow (CBF) and brainECF volume modestly affected the rate of BBB drug transport

Summary

Introduction

Both the rate and extent of central nervous system (CNS) unbound drug transport determine CNS concentration–time profiles of the unbound drug (PK) [1]. PK at the CNS target sites in the brain extracellular fluid (brainECF ) and brain intracellular fluid (brainICF ) is a function of plasma PK, drug transport across the blood–brain barrier (BBB), and intra-brain distribution Such PK processes result from the combination of the drug physicochemical properties and the physiological characteristics of the CNS [2,3]. Pericytes and astrocyte end feet ensure a complete coverage of the brain microvascular endothelial cells, while the basement membrane surrounds the endothelial cells and pericytes, separating them from each other and from the astrocytes end feet All together, these cells ensure the physical integrity of the BBB against the foreign plasma molecules. The brain tissue composition and active cellular membrane transporters further determine the unbound drug PK in the different brain compartments, while different pH values of the CNS compartments govern, for acids and bases, the extent of ionization [2]

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