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. 2021 Jan 13;13(1):95.
doi: 10.3390/pharmaceutics13010095.

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  1 , Elizabeth C M de Lange  1
Affiliations

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 et al. Pharmaceutics. .

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.

Keywords: CNS diseases; blood–brain barrier; brain pharmacokinetics; passive transport.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
LeiCNS-PK3.0 model structure. The central nervous system (CNS) model connects to the plasma via cerebral blood flow. LeiCNS-PK3.0 accounts for the brain and cerebrospinal fluid (CSF) compartments, the presence of the blood–brain barrier (BBB) and blood–CSF barriers, drug transport across the barriers and within the CNS, and physiological process such as non-specific binding and the effect of pH on drug ionization and on its passive transport.
Figure 2
Figure 2
Simulated concentration–time profiles of selected drugs at physiological and pathophysiological values of CBF, tight junction paracellular pore radius (pararadius), brainECF volume, pHECF, and pHICF. Pararadius affected the rate and extent of passive drug transport across the BBB, pHECF and pHICF affected the brainECF and brainICF unbound drug concentration-time profile (PK), whereas cerebral blood flow and brainECF volume had a very modest (if any) effect. The fixed plasma PK used excludes the involvement of plasma PK in the observed changes.
Figure 3
Figure 3
Heatmaps summarizing the effect of pathophysiological changes of CBF, tight junction paracellular pore radius (pararadius), brainECF volume, pHECF, and pHICF on brain pharmacokinetic parameters: Cmax, Tmax, AUC, Kpuu,ECF, and Kpuu,cell. Cmax and Tmax define the rate of BBB drug transport, while AUC and Kpuu define the extent of drug transport. Effect of pathophysiological changes remain drug (class) specific. Similar to the concentration–time profiles, pararadius, pHECF, and pHICF had a profound effect on brain pharmacokinetics compared to the minor effect of cerebral blood flow and brainECF volume. The fixed plasma PK used excludes the involvement of plasma PK in the observed changes.
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