Introduction
Interest in brain and central nervous system (CNS) diseases has surged in recent years, driven by an aging population and the rising prevalence of neurodegenerative disorders. This increased focus, coupled with the acceleration of new drug development, has underscored the necessity of understanding neuropharmacokinetics (neuroPK) beyond traditional pharmacokinetics. NeuroPK specifically addresses the challenges posed by the blood-brain barrier (BBB) and the unique environment of the CNS, offering insights into the absorption, distribution, metabolism, and excretion of drugs within the brain. The complexity of the CNS and the selective permeability of the BBB make it imperative to develop targeted delivery strategies and therapeutic agents that can effectively reach the brain and exert their intended effects [1].
Recent trends in neuroPK have seen significant advancements, particularly in the areas of drug delivery systems and personalized medicine. Innovative approaches such as nanoparticle-based delivery systems, prodrug strategies, and receptor-mediated transcytosis (RMT) have been developed to enhance drug delivery across the BBB. Nanotechnology, for example, offers a promising avenue for delivering therapeutic agents directly to the brain, improving drug stability, targeting, and bioavailability [2]. Additionally, the use of advanced imaging techniques, such as magnetic resonance imaging (MRI) and positron emission tomography (PET), has improved our ability to visualize drug distribution and efficacy in the CNS. The integration of artificial intelligence and big data analytics into neuroPK has further enabled personalized treatment plans, optimizing drug dosage based on individual genetic profiles and disease characteristics [3].
This review aims to provide a comprehensive overview of the current state and future directions in neuroPK. The discussion is divided into four main sections: basic concepts, methodologies, clinical applications, and advanced strategies for CNS drug delivery. The first section explores the foundational principles of neuroPK, including the structure and function of the BBB and key pharmacokinetic parameters. The second section delves into the various methodologies employed in neuroPK research, such as in vitro and in vivo models, microdialysis, and advanced imaging techniques. The third section examines the clinical applications of neuroPK, focusing on the treatment of CNS diseases with antipsychotic drugs, chemotherapy for brain tumors, and drugs for neurodegenerative diseases. Finally, the review addresses the advances in the field, including the development of new drug delivery systems and the integration of personalized medicine into clinical practice. Through this comprehensive analysis, the review seeks to highlight the importance of neuroPK in advancing the treatment of CNS disorders and to identify future research directions that could enhance therapeutic outcomes.
Basic Concepts of Neuropharmacology
Blood-brain barrier
The BBB is a critical structure of the CNS that maintains homeostasis of the brain’s environment. It acts as a gatekeeper, regulating the entry and exit of substances to protect the brain from toxins while allowing essential nutrients to pass through. This selective permeability poses a significant challenge for drug delivery to the brain, making the study of the BBB essential in neuroPK.
The BBB is composed of densely packed endothelial cells, astrocyte terminals, and surrounding cells that form a barrier restricting the passage of most molecules. Endothelial cells make up the cerebral microvasculature and are connected by tight junctions that restrict cell-to-cell movement. These tight junctions prevent the passage of large, hydrophilic molecules. Astrocyte endings, which are extensions of astrocytes, surround the blood vessels and help regulate the function of endothelial cells [4]. Pericytes, which surround the endothelial cells, contribute to the stability of the barrier and regulation of blood flow [5]. The selective permeability of the BBB is crucial for protecting the brain but also presents a significant barrier to drug delivery, limiting the effectiveness of many CNS therapies [6] (Figure 1).
There are several mechanisms by which substances can cross the BBB. Small lipophilic molecules can diffuse passively across the endothelial cell membrane. Transporter-mediated crossing of the BBB involves transport proteins that facilitate the movement of certain molecules, such as glucose and amino acids [7]. Larger molecules, such as insulin, can cross the BBB through RMT, while absorption-mediated transcytosis involves the uptake of cationic proteins and other molecules through electrostatic interactions with the cell membrane [8]. Efflux transporters, such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), actively expel a variety of substances, lowering their concentrations in the brain [9] (Figure 2).
The BBB plays an important role in neuroPK by influencing drug absorption, distribution, metabolism, and excretion within the CNS. Understanding the dynamics of drug transport across the BBB is essential for developing effective CNS therapies. In neuroPK, several key parameters are considered, including the brain-to-plasma ratio (Kp), which represents the extent of drug distribution in the brain relative to plasma, and the unbound brain-to-plasma ratio (Kp,uu), which reflects the unbound (active) drug concentration in the brain relative to plasma [10]. Additionally, rate constants (Kin and Kout) describe the rate at which drugs enter and leave the brain [11].
Pharmacokinetic parameters in the central nervous system
Absorption
Absorption refers to how a drug enters the bloodstream. For CNS drugs, effective absorption often hinges on the drug’s ability to cross the BBB, a selective barrier that protects the brain from harmful substances. The BBB restricts the passage of most drugs. As a result, drugs intended for CNS use must either be small and lipophilic to passively diffuse across the BBB or be designed to utilize specific transport mechanisms such as carrier-mediated transport or RMT. For example, studies have shown that lipophilic drugs like diazepam can cross the BBB more easily due to their high lipid solubility [12]. Additionally, RMT can be leveraged to transport larger molecules, such as antibodies, across the BBB by targeting specific receptors like the transferrin receptor (TfR) [13].
Distribution
Once absorbed, a drug must be distributed to its site of action within the brain. The volume of distribution (Vd) describes the extent to which a drug disperses throughout the body’s compartments. In the context of the CNS, the distribution is significantly influenced by the drug’s ability to penetrate the BBB and its binding affinity to brain tissues. Drugs with high brain tissue affinity, such as antipsychotics, often have a large Vd in the CNS, indicating extensive distribution within the brain [14]. Moreover, imaging techniques like PET have been employed to visualize drug distribution in the brain, providing valuable data on the pharmacokinetics of CNS drugs [15].
Metabolism
Metabolism involves the biotransformation of drugs, primarily in the liver, but also within the brain. The elimination rate constant (κ) and the formation of metabolites (both active and inactive) are crucial in determining the duration and intensity of a drug’s action. For CNS drugs, understanding brain metabolism is essential as it can influence both efficacy and safety. Enzymatic activity within the brain can alter the pharmacokinetic profile of a drug, affecting its therapeutic outcomes. For instance, cytochrome P450 enzymes, present in both the liver and brain, play a significant role in the metabolism of various psychotropic drugs. Additionally, studies have highlighted the importance of brain-specific enzymes such as monoamine oxidase in the metabolism of neurotransmitters and certain CNS-active drugs [16].
Excretion
Excretion is the process of removing drugs and their metabolites from the body, predominantly through the kidneys or bile. For CNS drugs, the clearance rate (Cl) and half-life (t1/2) are vital for maintaining therapeutic levels within the brain. These parameters determine how frequently a drug needs to be administered to maintain efficacy. Drugs with longer half-lives require less frequent dosing, which can enhance patient compliance. Renal excretion plays a significant role in the elimination of many CNS drugs, but it is important to note that some drugs and their metabolites may also be eliminated through biliary excretion [17]. Furthermore, efflux transporters at the BBB such as P-gp can actively transport drugs back into the bloodstream, thereby influencing CNS clearance and overall pharmacokinetics [18].
Determining drug concentration in the brain
Understanding drug concentration in the brain involves several important pharmacokinetic parameters, including the partition coefficient (Kp), unbound partition coefficient (Kp,u and Kp,uu), unbound volume of distribution in the brain (Vu,brain), and clearance rates (CLin and CLout).
The partition coefficient (Kp) describes the total brain-to-plasma concentration ratio at a steady state. This parameter helps determine the extent of drug distribution within the brain relative to the plasma.
The partition coefficient (Kp,u) compares total brain drug concentrations with unbound plasma drug concentrations. This ratio provides insight into the fraction of the drug that is pharmacologically active within the brain.
In contrast, the unbound partition coefficient (Kp,uu) represents the ratio of unbound drug concentration in brain interstitial fluid (ISF) to that in plasma. This parameter is crucial for understanding the bioavailability of the drug at its target site within the CNS.
The unbound volume of distribution in the brain (Vu,brain) describes the relationship between total drug concentration in the brain and unbound drug concentration in brain ISF. This equation helps quantify the distribution of unbound drug within the brain tissue.
Clearance rates are vital for understanding drug kinetics within the brain. Influx clearance (CLin) describes the rate at which a drug enters the brain. Conversely, efflux clearance (CLout) describes the rate at which a drug exits the brain. These parameters help determine the dynamic equilibrium between drug entry and exit from the brain.
At a steady state, the rate of drug concentration in brain ISF can be described by:
This relationship can be rearranged to determine the unbound partition coefficient. This equation highlights the importance of both influx and efflux mechanisms in maintaining drug levels within the brain.
Understanding these pharmacokinetic parameters allows for more accurate predictions of drug behavior within the CNS, facilitating the design of drugs with optimal therapeutic effects and minimal side effects. The partition coefficient (Kp) provides a general understanding of how well a drug distributes into the brain but does not account for the pharmacologically active fraction of the drug, which is better represented by the unbound partition coefficient (Kp,u and Kp,uu) [19,20].
The unbound volume of distribution in the brain (Vu,brain) is particularly important in quantifying the extent to which unbound drug permeates the brain tissue. This helps in understanding the drug’s potential efficacy at its target site within the CNS. For example, drugs with a high Vu,brain are more likely to be effective in treating CNS disorders because they can reach higher concentrations within the brain tissue.
Clearance rates (CLin and CLout) provide insight into the dynamics of drug entry and removal from the brain. These parameters are crucial for designing dosing regimens that maintain therapeutic drug levels within the CNS. For instance, drugs with high efflux rates (CLout) may require higher or more frequent dosing to achieve and maintain effective concentrations within the brain.
These pharmacokinetic parameters are essential for developing CNS-targeted therapies. By understanding and manipulating these variables, researchers can enhance drug delivery to the brain, improve therapeutic outcomes, and minimize adverse effects [1].
Methodologies in Neuropharmacokinetics
In vitro and ex vivo models
In vitro models
In vitro models utilize cell cultures and brain slices to study drug effects on a cellular and molecular level. Techniques such as patch-clamp electrophysiology, calcium imaging, and fluorescence microscopy allow researchers to examine drug-receptor interactions, ion channel activities, and intracellular signaling pathways. For example, patch-clamp electrophysiology can measure ion currents through individual ion channels, providing detailed insights into how drugs affect neuronal activity [21]. Calcium imaging techniques enable the visualization of calcium fluxes in neurons, which are crucial for understanding drug-induced changes in neuronal excitability and signaling [22]. Fluorescence microscopy allows for the visualization of specific proteins and cellular structures, aiding in the investigation of drug-target interactions at the molecular level [23].
Ex vivo models
Ex vivo techniques such as brain slice uptake and binding studies maintain the architecture and cellular composition of brain tissue, providing a more physiologically relevant context than in vitro models. These studies help elucidate the mechanisms of drug uptake, distribution, and binding within the brain. For instance, brain slice uptake studies can reveal how drugs penetrate and distribute within brain tissue, while binding studies can identify specific drug-receptor interactions. These methods are critical for understanding the initial stages of drug action and for screening potential CNS-active compounds.
In vivo models
Animal models, especially rodents, are indispensable in neuroPK for understanding the systemic effects of drugs. These models allow for the study of behavioral, physiological, and biochemical responses to pharmacological agents. Techniques like microdialysis enable real-time measurement of drug concentrations in specific brain regions, providing insight into the dynamics of drug distribution and metabolism within the CNS. Microdialysis involves inserting a probe with a semipermeable membrane into a specific brain region. Perfusion fluid is passed through the probe, allowing molecules from the extracellular fluid to diffuse into the perfusion fluid. The collected samples are then analyzed to determine drug concentrations and neurotransmitter levels in the brain [24].
Advanced imaging techniques
Positron emission tomography
PET imaging is a noninvasive technique that provides quantitative data on drug distribution and receptor binding in the living brain. Radiolabeled compounds that target specific receptors or transporters are administered, and their distribution is visualized using PET. This technique is critical for understanding the kinetics and dynamics of drug action and for translating preclinical findings to clinical applications. For example, PET can be used to track the distribution of antipsychotic drugs in the brain, helping to optimize dosing regimens and improve therapeutic outcomes [25].
Functional magnetic resonance imaging
Functional MRI (fMRI) is a pivotal noninvasive tool in neuroPK, providing detailed insights into drug effects on brain function through blood-oxygen-level-dependent (BOLD) changes. The methodology involves baseline scans, drug administration, and subsequent serial scans to monitor dynamic changes in brain activity. These data are analyzed to develop pharmacokinetic-pharmacodynamic models that elucidate the relationship between drug exposure and its effects on brain activity [26]. fMRI’s high spatial and temporal resolution allows precise tracking of drug-induced changes in specific brain regions and offers functional insights into drug mechanisms and therapeutic effects [27]. However, challenges such as the interpretation of indirect BOLD signals and sensitivity to subject movement can complicate data analysis. Despite these limitations, advancements in fMRI technology and analytical methods, including resting-state fMRI and machine learning, have significantly enhanced its application in neuroPK, aiding in the development of effective neuropharmacological therapies [28].
Optogenetics and chemogenetics
Optogenetics and chemogenetics allow for the precise control of neuronal activity using light (optogenetics) or engineered receptors activated by designer drugs (chemogenetics). By selectively modulating specific neurons, researchers can dissect the neural circuits involved in drug action, providing a deeper understanding of the neurobiological mechanisms underlying pharmacological effects. Optogenetics involves the use of light-sensitive proteins to control neuronal activity with light, enabling the study of neuronal circuits with high temporal precision [29]. Chemogenetics uses engineered receptors that can be selectively activated by synthetic ligands, allowing for targeted modulation of neuronal activity without the need for light [30].
Molecular and genetic techniques
CRISPR-Cas9 and gene editing
CRISPR-Cas9 technology has revolutionized neuroPK by enabling precise genetic modifications. This technique allows for the creation of animal models with specific genetic mutations, facilitating the study of the role of individual genes in drug responses and the development of targeted therapies for genetic CNS disorders. CRISPR-Cas9 can be used to knock out or modify specific genes, providing insight into their functions and how they influence drug action [31].
RNA sequencing and transcriptomics
RNA sequencing and transcriptomics provide comprehensive insights into gene expression changes induced by drugs. By analyzing the RNA transcripts in each tissue, researchers can identify molecular pathways affected by pharmacological treatments, uncovering potential biomarkers and therapeutic targets. These techniques allow for the quantification of gene expression levels and the identification of differentially expressed genes in response to drug treatment, providing a detailed understanding of the molecular effects of drugs [32].
Computational models and simulations
In silico screening and molecular docking
Computational approaches such as in silico screening and molecular docking predict the interactions between drugs and their targets. These methods accelerate the drug discovery process by identifying promising candidates and optimizing their chemical structures before experimental validation. Molecular docking involves predicting the preferred orientation of a drug when it binds to its target, providing insights into the binding affinity and specificity [33].
Physiologically based pharmacokinetic modeling
Physiologically based pharmacokinetic (PBPK) models use mathematical descriptions of physiological processes to predict the absorption, distribution, metabolism, and excretion of drugs. These models integrate data from in vitro and in vivo studies to simulate drug behavior in humans, facilitating dose optimization and reducing the need for extensive clinical trials. PBPK modeling can predict drug concentrations in various tissues over time, helping to optimize dosing regimens and improve therapeutic outcomes [34].
Applications in Central Nervous System Drugs
Antipsychotic drugs
Haloperidol
Haloperidol, a first-generation antipsychotic, is widely studied for its pharmacokinetic properties within the CNS. Its ability to cross the BBB primarily occurs through passive diffusion, although there is evidence suggesting active transport mechanisms in specific brain regions. The regional BBB transport of haloperidol varies significantly, with the highest penetration observed in the frontal cortex, striatum, and hippocampus, indicating potential active uptake mechanisms. Haloperidol’s distribution is heavily influenced by its high binding affinity to D2 receptors in the brain, which is essential for its therapeutic efficacy [35]. The unbound brain concentrations of haloperidol are critical for achieving its antipsychotic effects, as studies have shown that receptor occupancy in various brain regions directly impacts clinical outcomes and side effects, such as extrapyramidal symptoms [36] (Table 1).
Clozapine
Clozapine, a second-generation antipsychotic, is notable for its broad receptor binding profile and complex neuroPK characteristics. Clozapine crosses the BBB efficiently, but its transport is significantly influenced by P-gp efflux mechanisms, particularly in regions such as the cerebellum. Unlike other antipsychotics, clozapine demonstrates relatively less regional variability in BBB transport. However, its Kp,uu,ROI values suggest significant efflux in certain brain areas. Clozapine binds variably to brain tissue, with the highest unbound fractions in the hypothalamus and striatum and accumulates significantly in intracellular compartments due to lysosomal trapping. These regional differences in brain distribution and receptor occupancy are crucial for understanding its therapeutic effects and side effects, such as agranulocytosis and sedation [37].
Olanzapine
Olanzapine, another second-generation antipsychotic, exhibits a favorable BBB transport profile, with Kp,uu,ROI values close to unity in most brain regions, indicating efficient passive diffusion. In specific regions like the frontal cortex and striatum, olanzapine shows evidence of active uptake mechanisms, as indicated by Kp,uu,ROI values exceeding 1. Olanzapine’s brain distribution is characterized by significant intracellular accumulation, influenced by both its physicochemical properties and active transport mechanisms. Unbound concentrations of olanzapine in various brain regions are vital for its receptor occupancy, particularly at 5-HT2A and D2 receptors [35]. This regional variability in receptor occupancy plays a critical role in its effectiveness in treating schizophrenia and its side effect profile, including weight gain and metabolic disturbances.
Risperidone
Risperidone, along with its active metabolite paliperidone, demonstrates complex neuroPK profiles influenced by P-gp–mediated efflux mechanisms. Both risperidone and paliperidone show significant regional variability in BBB transport, with the highest brain penetration in the frontal cortex and the lowest in the cerebellum [38]. This regional variability is essential for understanding their differential effects on various CNS regions. Risperidone and paliperidone exhibit significant tissue binding and intracellular accumulation, particularly in the cortex and striatum. The unbound concentrations of these drugs in these regions are crucial for achieving therapeutic effects at 5-HT2A and D2 receptors. Regional differences in brain distribution and receptor occupancy are key to their efficacy in treating schizophrenia and their side effect profiles, such as hyperprolactinemia and extrapyramidal symptoms.
Quetiapine
Quetiapine is distinguished by its broad receptor binding profile and relatively complex neuroPK characteristics. It crosses the BBB through passive diffusion, with moderate regional variability in transport. The highest Kp,uu,ROI values are observed in the cortex and hippocampus, whereas the cerebellum exhibits significant efflux, likely mediated by P-gp. Quetiapine’s brain tissue binding is moderately variable, with notable intracellular accumulation in the cortex and striatum. Unbound concentrations of quetiapine are crucial for therapeutic effects at 5-HT2A and D2 receptors [39]. The regional differences in quetiapine’s brain distribution and receptor occupancy are significant for its clinical efficacy and side effect profile, including sedation and orthostatic hypotension.
Chemotherapy for brain tumors
Temozolomide
Temozolomide (TMZ) is an oral alkylating agent widely used for treating glioblastoma multiforme (GBM) and other malignant gliomas. Its ability to cross the BBB makes it effective in targeting brain tumors. After oral administration, TMZ is rapidly absorbed, achieving peak plasma concentrations within 30–90 minutes post-dose [40]. The drug undergoes spontaneous hydrolysis at physiological pH to its active metabolite, 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide, which then alkylates DNA and induces tumor cell death [41]. The distribution of TMZ in the brain is influenced by its ability to cross the BBB and its subsequent diffusion into the brain interstitium. Intracerebral microdialysis (ICMD) data indicate that TMZ achieves significant concentrations in the brain interstitium, crucial for its therapeutic efficacy against glioblastomas [42].
Recent studies have employed ICMD to monitor TMZ concentrations in the brain interstitium, providing insights into its neuroPK. ICMD data have shown that TMZ achieves therapeutic concentrations in the brain, correlating with its efficacy in prolonging survival in GBM patients. Additionally, model-based pharmacokinetic analyses using nonlinear mixed-effects modeling programs have helped refine dosing regimens to maintain effective drug levels in cerebrospinal fluid (CSF) and plasma [43]. The neuroPK profile of TMZ shows that its peak concentration in the brain interstitium is delayed compared to plasma, with Tmax values occurring at around 2 hours. This delayed peak suggests that administration timing relative to radiotherapy can be optimized to enhance radiosensitization.
Bevacizumab
Bevacizumab, a recombinant humanized monoclonal antibody that targets vascular endothelial growth factor, has shown significant efficacy in the treatment of various malignancies, including glioblastomas. Its ability to inhibit angiogenesis makes it a critical therapeutic agent for tumors reliant on vascular supply. Understanding the neuroPK of bevacizumab is essential for optimizing its therapeutic efficacy and minimizing adverse effects. Studies have demonstrated that bevacizumab can cross the BBB to a limited extent, impacting its distribution and effectiveness in targeting brain tumors. For example, the intraocular pharmacokinetics of bevacizumab reveal its half-life in the vitreous humor, highlighting the importance of dosage optimization for effective CNS penetration [44].
ICMD studies provide valuable insights into the distribution of bevacizumab within the brain interstitium. The pharmacokinetics of intravitreal bevacizumab show its clearance rates, suggesting potential parallels in CNS applications [45]. Additionally, comparisons of the pharmacokinetics of bevacizumab administered via different ocular routes provide a framework for understanding its distribution in CNS tissues [46]. These findings collectively underscore the importance of continued research to refine bevacizumab delivery strategies for optimal CNS tumor management.
Abemaciclib
Abemaciclib, a selective CDK4/6 inhibitor, shows promising neuroPK properties for treating CNS malignancies. Studies have demonstrated that abemaciclib effectively crosses the BBB and achieves therapeutic concentrations in the brain. Tolaney et al. [47] reported significant brain exposure and active metabolites in patients with brain metastases from hormone receptor-positive breast cancer, indicating potential efficacy in CNS treatment. Similarly, Raub et al. [48] confirmed abemaciclib’s ability to penetrate the CNS and exert antitumor activity in preclinical models.
Mechanistic and pharmacokinetic modeling studies further elucidate the drug’s CNS pharmacokinetics, aiding in optimizing dosing regimens [49,50]. Additionally, research by Martínez-Chávez et al. [51] highlights the roles of multidrug efflux transporters and CYP3A in influencing abemaciclib’s brain penetration and overall pharmacokinetics. These studies collectively underscore abemaciclib’s potential for treating brain metastases and primary brain tumors, making it a compelling candidate in neuro-oncology.
Methotrexate
Methotrexate (MTX) is a key chemotherapeutic agent used in the treatment of various cancers, including acute lymphoblastic leukemia and non-Hodgkin’s lymphoma. Its ability to penetrate the CNS is critical for treating CNS malignancies. MTX crosses the BBB and distributes within the CSF. High-dose MTX therapy is often employed to ensure adequate CNS penetration, as shown by Stoller et al. [52], who noted significant interpatient variability in plasma and CSF levels, indicating the necessity for personalized dosing to balance efficacy and toxicity.
The intrathecal administration of MTX, which involves direct injection into the CSF, bypasses the BBB and achieves higher concentrations in the CNS. Bleyer and Dedrick studied the pharmacokinetics of intrathecal MTX, highlighting its distribution, peak concentration times, and clearance rates within the CSF. These pharmacokinetic properties are crucial for maximizing the drug’s antitumor effects while minimizing systemic toxicity [53]. Moreover, Westerhout et al. [54] demonstrated that the disease state significantly influences MTX’s CNS pharmacokinetics, suggesting that patients with compromised BBB integrity due to tumor infiltration may experience different drug distribution and clearance profiles compared to healthy individuals. Understanding these dynamics helps optimize MTX dosing regimens, enhancing therapeutic outcomes in CNS malignancies.
Drugs for neurodegenerative diseases
Donepezil
Donepezil, a cholinesterase inhibitor, is widely used in the treatment of Alzheimer disease (AD). It efficiently crosses the BBB due to its lipophilic nature and low molecular weight. It reaches therapeutic concentrations in the brain and is metabolized primarily by CYP2D6 and CYP3A4. The long half-life of approximately 70 hours allows for once-daily dosing, making it suitable for sustained management of AD symptoms. Donepezil enhances cholinergic transmission by inhibiting acetylcholinesterase, thereby increasing acetylcholine levels in the synaptic cleft. Its distribution is significant in the cortex and hippocampus, regions critical for memory and cognitive functions, aligning with its therapeutic effects. NeuroPK studies show a high brain-to-plasma ratio for donepezil, indicating significant CNS penetration and sustained action within the brain [55,56].
Memantine
Memantine, an N-methyl-ᴅ-aspartate receptor antagonist used in moderate to severe AD, regulates glutamate activity to prevent excitotoxicity. Memantine efficiently crosses the BBB due to its moderate lipophilicity. It has a half-life of 60-80 hours and is primarily excreted unchanged via the kidneys, thus minimizing hepatic metabolism. Memantine’s extensive brain distribution, particularly in regions with high glutamatergic activity, is crucial for its neuroprotective effects. It regulates synaptic plasticity and prevents neuronal damage by inhibiting excessive calcium influx, thereby stabilizing neuronal function and improving cognitive outcomes in AD patients. The drug exhibits a linear relationship between dose and plasma concentration, ensuring consistent CNS penetration that correlates with its neuroprotective effects [57,58].
Levodopa
Levodopa is the cornerstone treatment for Parkinson disease (PD), functioning as a precursor to dopamine. It is converted to dopamine in the brain by aromatic L-amino acid decarboxylase (AADC). Coadministration with carbidopa, an AADC inhibitor, enhances levodopa’s CNS availability by preventing its peripheral metabolism. Levodopa is rapidly absorbed, with peak plasma concentrations occurring within 1–2 hours post-dose. Its effectiveness is limited by the BBB and its short half-life, necessitating frequent dosing. Levodopa’s effectiveness is linked to its ability to replenish dopamine levels in the striatum. The neuroPK profile of levodopa shows high variability, influenced by factors such as gastric emptying and dietary amino acids, which affect its absorption and bioavailability [59].
Riluzole
Riluzole, approved for the treatment of amyotrophic lateral sclerosis (ALS), is believed to inhibit glutamate release and block voltage-gated sodium channels. Riluzole is highly lipophilic, facilitating efficient BBB penetration. It has a half-life of 12 to 15 hours and undergoes extensive hepatic metabolism via CYP1A2, with inactive metabolites excreted via urine. Riluzole is rapidly absorbed, achieving peak plasma levels within 1 to 1.5 hours. Its neuroPK is characterized by effective CNS penetration, ensuring adequate concentrations to reduce glutamate excitotoxicity. Its significant brain distribution, especially in the motor cortex and spinal cord, is crucial for its efficacy in ALS. Studies show significant CSF concentrations of riluzole, correlating with its efficacy in slowing ALS progression [60-62].
Aducanumab
Aducanumab is a monoclonal antibody designed to selectively target aggregated amyloid-beta (Aβ) plaques in AD, with the aim of modifying disease progression by reducing Aβ deposition [63]. It follows a two-compartment pharmacokinetic model with first-order elimination and has an effective half-life of approximately 24.8 days [63,64]. Although preclinical studies indicate that focused ultrasound (FUS) can temporarily open the BBB and increase CNS penetration of large-molecule therapeutics, direct evidence of this effect specifically for aducanumab remains limited, highlighting the need for further investigation.
Clinically, aducanumab has shown a dose-dependent reduction in Aβ plaques (particularly at 10 mg/kg), as measured by changes in standardized uptake value ratio on PET imaging [63,64]. However, the degree to which this translates into cognitive improvement is still under debate. In addition, amyloid-related imaging abnormalities—especially in carriers of the apolipoprotein E ε4 allele—raise significant safety considerations [63-65]. Future research efforts will need to refine dosing regimens, explore adjunct strategies (such as FUS-mediated BBB modulation), and evaluate overall clinical effectiveness to maximize aducanumab’s therapeutic potential in AD.
Other promising drugs for sleep and epilepsy
Suvorexant
Suvorexant is a dual orexin receptor antagonist (DORA) approved for the management of insomnia, acting by selectively blocking orexin-1 and orexin-2 receptors to reduce wakefulness [66]. Its neuroPK properties are characterized by rapid absorption (time to peak plasma concentration ~2 hours) and an elimination half-life of approximately 12–19 hours, supporting once-daily dosing. The drug undergoes extensive hepatic metabolism primarily via CYP3A4, with a minor contribution from CYP2C19, producing inactive metabolites that do not appreciably cross the BBB [67,68]. Physicochemical profiles, including a molecular weight near 450 Da and a logP of ~3 to 4, further favor BBB penetration and centrally mediated effects. Overall, these features result in a relatively clean safety profile, minimal rebound insomnia, and low potential for complex CNS drug-drug interactions when used within recommended guidelines.
Cenobamate
Cenobamate is an antiseizure medication indicated for the treatment of focal onset seizures in adults. Its dual mechanism of action involves inhibiting persistent sodium currents and positively modulating GABA-A receptor-mediated inhibitory neurotransmission, leading to decreased neuronal excitability. The drug is rapidly absorbed (peak plasma concentrations typically within 1–4 hours) and exhibits a long elimination half-life of about 50–60 hours, making once-daily dosing feasible [69]. Metabolism primarily occurs via hepatic pathways involving both cytochrome P450 (particularly CYP2E1 and other minor pathways) and uridine diphosphate–glucuronosyltransferase (UGT) enzymes, allowing for extensive biotransformation before renal excretion. Cenobamate can induce certain CYP enzymes (e.g., CYP3A4) while inhibiting others (e.g., CYP2C19), necessitating careful monitoring of concomitant medications [70]. Its favorable BBB penetration contributes to robust seizure control, although a gradual titration schedule is recommended to mitigate adverse effects such as sedation and to reduce the risk of drug-drug interactions.
Advanced Strategies in Central Nervous System Drug Delivery
Nanoparticle-based delivery system
Nanoparticles facilitate CNS drug delivery through several mechanisms. First, nanoparticles can exploit the enhanced permeability and retention effect, where they preferentially accumulate in tumor tissues or inflamed areas with leaky vasculature. This property is particularly useful for targeting brain tumors and other CNS pathologies with compromised BBB integrity. Second, nanoparticles can be surface-modified with ligands such as antibodies, peptides, or small molecules that bind specifically to receptors on the BBB or CNS cells. This active targeting enhances the selective delivery of drugs to desired sites within the brain, improving therapeutic efficacy and reducing off-target effects. Third, certain ligands on the surface of nanoparticles can engage with receptors on endothelial cells of the BBB, facilitating RMT. This mechanism allows nanoparticles to traverse the BBB and release their cargo directly into the brain parenchyma. Last, cell-penetrating peptides (CPPs) can be conjugated to nanoparticles to enhance their ability to cross cellular membranes, including the BBB. CPPs facilitate the internalization of nanoparticles into brain endothelial cells, promoting their subsequent translocation into the CNS (Table 2).
Polymeric nanoparticles
Polymeric nanoparticles are formed from biodegradable and biocompatible polymers such as polylactic acid, polyglycolic acid (PGA), and their copolymer polylactic-co-glycolic acid (PLGA). These nanoparticles can encapsulate both hydrophilic and hydrophobic drugs, providing controlled release and protection from degradation. Patel et al. [71] demonstrated that polymeric nanoparticles could be engineered to cross the BBB and deliver therapeutic agents directly to brain tissues, providing sustained and controlled drug release, which improved therapeutic outcomes in preclinical models of brain diseases.
Lipid-based nanoparticles
Lipid-based nanoparticles, such as liposomes and solid lipid nanoparticles, have a core composed of lipids surrounded by a phospholipid bilayer. These nanoparticles can encapsulate drugs in their core or within the bilayer, providing a versatile platform for drug delivery. Singh and Lillard [72] reported that liposomes could be functionalized by targeting ligands such as antibodies or peptides to enhance their specificity for BBB receptors, improving their uptake and retention in the brain. This approach has shown significant promise in delivering chemotherapeutic agents and neuroprotective drugs to the CNS.
Metallic nanoparticles
Metallic nanoparticles, such as gold and silver nanoparticles, have unique optical and electronic properties that can be exploited for drug delivery and imaging. These nanoparticles can be coated with biocompatible materials and functionalized with targeting ligands. Ding et al. [73] explored the use of gold nanoparticles to enhance the delivery of drugs to the brain, demonstrating that their surface could be modified with polyethylene glycol and targeting ligands to improve stability, reduce toxicity, and increase BBB penetration. These modifications allowed for efficient drug delivery and imaging of brain tumors in preclinical studies.
Dendrimers
Dendrimers are highly branched, tree-like macromolecules with a well-defined structure. They offer a high degree of surface functionality, allowing for the attachment of multiple drug molecules and targeting ligands. Previous study discussed that dendrimers could be engineered to enhance drug solubility and provide controlled release, making them suitable for CNS drug delivery. The precise control over their size and surface properties enables efficient crossing of the BBB and targeted delivery to specific brain regions, which has been demonstrated in models of neurodegenerative diseases and brain cancer [74].
Blood-brain barrier modulation
Focused ultrasound with microbubbles
FUS combined with microbubbles is an innovative technique for modulating the BBB to enhance drug delivery to the CNS. This method utilizes the mechanical effects of ultrasound waves on microbubbles, which are injected into the bloodstream [75]. When these microbubbles encounter the ultrasound field, they oscillate and produce mechanical forces that temporarily and reversibly disrupt the BBB, allowing therapeutic agents to penetrate the brain [76]. Clinical trials have demonstrated the potential of this technique to safely increase BBB permeability, facilitating the delivery of drugs to targeted brain regions [75]. Furthermore, this approach has been used to enhance neuromodulation and drug delivery, showcasing its versatility and efficacy [76].
The safety and efficacy of FUS with microbubbles have been extensively evaluated in preclinical and clinical studies [77]. In the context of brain tumors, this method significantly improves the delivery of chemotherapeutic agents to tumor sites, indicating its potential to enhance cancer treatment [77]. Advances in acoustic monitoring and control have been crucial in optimizing the parameters of FUS, ensuring consistent and safe BBB modulation. These advancements underscore the potential of FUS with microbubbles as a powerful tool for enhancing CNS drug delivery and advancing the treatment of neurological disorders [78].
Receptor-mediated transcytosis
RMT is a promising strategy for overcoming the BBB to enhance drug delivery to the CNS. The BBB, comprised of tightly joined endothelial cells, restricts the passage of most substances from the bloodstream into the brain, posing a significant challenge for treating neurological diseases. RMT leverages specific receptors on the BBB, such as TfR, insulin receptor, and low-density lipoprotein receptor, to transport therapeutic agents into the brain. This process involves the binding of ligands or therapeutic molecules to receptors on the luminal surface of endothelial cells, followed by endocytosis, transcellular transport, and release on the abluminal side. Studies, such as those by Sato et al. [79], have demonstrated the effectiveness of TfR-mediated transcytosis in delivering large-molecule therapeutics to the CNS.
Several strategies enhance RMT and improve drug delivery across the BBB. Ligand modification involves conjugating therapeutic agents with ligands that have a high affinity for BBB receptors, thereby increasing binding and transcytosis efficiency. Stanimirovic et al. [80] explored using bispecific antibodies to target multiple receptors simultaneously, enhancing transcytosis efficiency. Additionally, nanoparticle systems can incorporate ligands for RMT, improving drug delivery to brain capillary endothelial cells [81]. Receptor engineering, involving the modification of BBB receptors through genetic or pharmacological means, can also increase therapeutic agent uptake, further optimizing RMT for drug delivery [82]. These advancements highlight the potential of RMT in neuroPK, offering new avenues for treating CNS disorders.
Efflux transporter inhibition
Efflux transporters at BBB, such as P-gp, multidrug resistance-associated proteins (MRPs), and BCRP, play a crucial role in limiting the entry of therapeutic agents into the CNS. These transporters actively pump drugs out of the brain, which poses a significant challenge in treating neurological disorders and brain tumors. Inhibiting these efflux transporters has emerged as a promising strategy to enhance drug delivery to the CNS. Direct inhibitors like tariquidar and elacridar can block the drug-binding sites of P-gp and BCRP, while competitive inhibitors act as substrates that compete with therapeutic drugs for transporter binding. Additionally, downregulating transporter expression through genetic or pharmacological means can reduce their activity at the BBB, increasing drug accumulation in the brain [83].
Efflux transporter inhibition has significant therapeutic potential, particularly for brain tumors, epilepsy, and HIV-associated neurocognitive disorders. For instance, coadministering P-gp inhibitors with chemotherapeutic agents can enhance drug accumulation in brain tumor tissues, improving therapeutic outcomes. Similarly, inhibiting efflux transporters can improve the efficacy of antiepileptic drugs in resistant patients [84] and enhance the CNS delivery of antiretroviral drugs for treating HIV-associated neurocognitive disorders [85]. However, the clinical translation of efflux transporter inhibitors faces challenges such as ensuring safety and minimizing drug-drug interactions. Future research should focus on developing specific inhibitors, exploring combination therapies, and tailoring strategies to individual patients based on their genetic profile and disease characteristics.
Prodrug strategies
Prodrug strategies have emerged as a promising approach to enhance drug delivery to the CNS by modifying the pharmacokinetic and pharmacodynamic properties of therapeutic agents. The BBB is a significant obstacle in CNS drug delivery due to its selective permeability, which protects the brain but also prevents many therapeutic agents from entering. Prodrugs are pharmacologically inactive compounds that undergo enzymatic or chemical conversion in the body to release the active drug. This strategy can improve the solubility, stability, and permeability of drugs, facilitating their transport across the BBB. Recent advances in prodrug design have shown significant potential in enhancing CNS drug delivery for various neurological disorders.
Prodrugs can be designed using various strategies to enhance their pharmacokinetic properties. Increasing the lipophilicity of prodrugs can improve their passive diffusion across the BBB, as demonstrated by the palmitic ester prodrug of leucine5-enkephalin, which improved CNS delivery via enhanced lipophilicity [86]. Utilizing endogenous transporters at the BBB, such as peptide transporters or amino acid transporters, is another effective strategy. Amino acid prodrugs of valproic acid that utilized the LAT1 transporter resulted in extended brain exposure [87]. Additionally, prodrugs can be designed for enzymatic activation, ensuring site-specific drug release in the brain. For instance, 6-diazo-5-oxo-l-norleucine prodrugs were enzymatically converted to the active drug in the CNS, enhancing therapeutic efficacy [88].
Prodrug strategies have been explored for various therapeutic applications in neuroPK. In PD, prodrugs of dopamine and levodopa have been developed to improve BBB penetration and improve pharmacokinetics, significantly improving treatment outcomes [89]. For epilepsy, prodrugs of bumetanide were designed to enhance CNS delivery and efficacy [90]. In AD, the development of optimized prodrugs like ALZ-801 has shown promise in improving the pharmacokinetics and safety of treatments [91]. While prodrug strategies hold great promise, challenges such as ensuring stability, achieving specific CNS targeting, and obtaining regulatory approval remain. Future research should focus on optimizing prodrug design, understanding BBB transport mechanisms, and conducting clinical trials to validate their therapeutic potential.
Ongoing Clinical Trials
Recent efforts to optimize CNS drug delivery have included large-scale or multi-center clinical trials evaluating various strategies such as RMT and FUS. For example, a phase 2/3 study (NCT05371613) is currently investigating DNL310, an RMT-based enzyme replacement therapy for Hunter syndrome (MPS II), aiming to enhance BBB penetration of the therapeutic enzyme [92]. In recurrent glioblastoma, the SonoCloud device (NCT03744026) uses FUS to transiently open the BBB, potentially improving chemotherapeutic drug delivery [93]. Meanwhile, preliminary trials in AD (NCT03671889) have explored whether FUS can facilitate higher brain uptake of therapeutic agents, although more extensive phase III evaluations remain on the horizon [94].
Conclusion
The study of neuroPK is crucial for advancing the treatment of CNS disorders. The unique challenges posed by the BBB and the complex environment of the CNS necessitate specialized approaches to drug delivery and therapy. This review has highlighted the significant progress made in the field, particularly in the development of advanced drug delivery systems and innovative methodologies.
Despite these advancements, several challenges remain. Ensuring the long-term safety and biocompatibility of new delivery systems, overcoming regulatory hurdles, and addressing the variability in BBB permeability are critical issues that will require further research and innovation. Additionally, the ethical considerations and logistical complexities associated with personalized medicine require careful management.
In conclusion, the field of neuroPK holds immense potential for improving the treatment of CNS disorders. Continued interdisciplinary collaboration and technological advancements are essential to overcome current challenges and translate innovative strategies into effective clinical therapies. By focusing on the development of targeted delivery systems, personalized treatment plans, and comprehensive methodologies, researchers and clinicians can enhance the efficacy of CNS drugs, ultimately improving patient outcomes and quality of life.
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