Analysis of the contributing role of drug transport across biological barriers in the development and treatment of chemotherapy-induced peripheral neuropathy.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) represents a major unmet medical need that currently has no preventive and/or curative treatment. This is, among others, driven by a poor understanding of the contributive role of drug transport across biological barriers to target-site exposure. METHODS: Here, we systematically investigated the transport of 11 small-molecule drugs, both, associated and not with CIPN development, at conventional (dorsal root ganglia, sciatic nerve) and non-conventional (brain, spinal cord, skeletal muscle) CIPN sites. We developed a Combinatory Mapping Approach for CIPN, CMA-CIPN, combining in vivo and in vitro elements. RESULTS: Using CMA-CIPN, we determined the unbound tissue-to-plasma concentration ratio (Kp,uu) and the unbound intracellular-to-extracellular concentration ratio (Kp,uu,cell), to quantitatively assess the extent of unbound drug transport across endothelial interfaces and parenchymal cellular barriers of investigated CIPN-sites, respectively, in a rat model. The analysis revealed that unique pharmacokinetic characteristics underly time-dependent accumulation of the CIPN-positive drugs paclitaxel and vincristine at conventional (dorsal root ganglia and sciatic nerve) and non-conventional (skeletal muscle) CIPN sites. Investigated CIPN-positive drugs displayed intracellular accumulation contrary to CIPN-negative drugs nilotinib and methotrexate, which lacked this feature in all investigated tissues. CONCLUSIONS: Hence, high unbound drug intracellular and extracellular exposure at target sites, driven by an interplay of drug transport across the endothelial and parenchymal cellular barriers, is a predisposing factor to CIPN development for CIPN-positive drugs. Critical drug-specific features of unbound drug disposition at various CIPN- sites provide invaluable insights into understanding the pharmacological/toxicological effects at the target-sites which will inform new strategies for monitoring and treatment of CIPN.

Active Uptake of Oxycodone at Both the Blood-Cerebrospinal Fluid Barrier and The Blood-Brain Barrier without Sex Differences: A Rat Microdialysis Study.

BACKGROUND: Oxycodone active uptake across the blood-brain barrier (BBB) is associated with the putative proton-coupled organic cation (H+/OC) antiporter system. Yet, the activity of this system at the blood-cerebrospinal fluid barrier (BCSFB) is not fully understood. Additionally, sex differences in systemic pharmacokinetics and pharmacodynamics of oxycodone has been reported, but whether the previous observations involve sex differences in the function of the H+/OC antiporter system remain unknown. The objective of this study was, therefore, to investigate the extent of oxycodone transport across the BBB and the BCSFB in female and male Sprague-Dawley rats using microdialysis. METHODS: Microdialysis probes were implanted in the blood and two of the following brain locations: striatum and lateral ventricle or cisterna magna. Oxycodone was administered as an intravenous infusion, and dialysate, blood and brain were collected. Unbound partition coefficients (Kp,uu) were calculated to understand the extent of oxycodone transport across the blood-brain barriers. Non-compartmental analysis was conducted using Phoenix 64 WinNonlin. GraphPad Prism version 9.0.0 was used to perform t-tests, one-way and two-way analysis of variance followed by Tukey's or Sídák's multiple comparison tests. Differences were considered significant at p < 0.05. RESULTS: The extent of transport at the BBB measured in striatum was 4.44 ± 1.02 (Kp,uu,STR), in the lateral ventricle 3.41 ± 0.74 (Kp,uu,LV) and in cisterna magna 2.68 ± 1.01 (Kp,uu,CM). These Kp,uu values indicate that the extent of oxycodone transport is significantly lower at the BCSFB compared with that at the BBB, but still confirm the presence of active uptake at both blood-brain interfaces. No significant sex differences were observed in neither the extent of oxycodone delivery to the brain, nor in the systemic pharmacokinetics of oxycodone. CONCLUSIONS: The findings clearly show that active uptake is present at both the BCSFB and the BBB. Despite some underestimation of the extent of oxycodone delivery to the brain, CSF may be an acceptable surrogate of brain ISF for oxycodone, and potentially also other drugs actively transported into the brain via the H+/OC antiporter system.

Differential Blood-Brain Barrier Transport and Cell Uptake of Cyclic Peptides In Vivo and In Vitro.

The blood-brain barrier (BBB) poses major challenges to drug delivery to the CNS. SFTI-1 and kalata B1 are cyclic cell-penetrating peptides (cCPPs) with high potential to be used as scaffolds for drug delivery. We here studied their transport across the BBB and distribution within the brain to gauge the potential of these two cCPPs as scaffolds for CNS drugs. In a rat model, SFTI-1 exhibited, for a peptide, high extent of BBB transport with a partitioning of unbound SFTI-1 across the BBB, Kp,uu,brain, of 13%, while only 0.5% of kalata B1 equilibrated across the BBB. By contrast, kalata B1, but not SFTI-1, readily entered neural cells. SFTI-1, but not kalata B1, could be a potential CNS delivery scaffold for drugs directed to extracellular targets. These findings indicate that differences between the BBB transport and cellular uptake abilities of CPPs are crucial in the development of peptide scaffolds.

Understanding the Blood-Brain Barrier and Beyond: Challenges and Opportunities for Novel CNS Therapeutics.

This review addresses questions on how to accomplish successful central nervous system (CNS) drug delivery (i.e., having the right concentration at the right CNS site, at the right time), by understanding the rate and extent of blood-brain barrier (BBB) transport and intra-CNS distribution in relation to CNS target site(s) exposure. To this end, we need to obtain and integrate quantitative and connected data on BBB using the Combinatory Mapping Approach that includes in vivo and ex vivo animal measurements, and the physiologically based comprehensive LEICNSPK3.0 mathematical model that can translate from animals to humans. For small molecules, slow diffusional BBB transport and active influx and efflux BBB transport determine the differences between plasma and CNS pharmacokinetics. Obviously, active efflux is important for limiting CNS drug delivery. Furthermore, liposomal formulations of small molecules may to a certain extent circumvent active influx and efflux at the BBB. Interestingly, for CNS pathologies, despite all reported disease associated BBB and CNS functional changes in animals and humans, integrative studies typically show a lack of changes on CNS drug delivery for the small molecules. In contrast, the understanding of the complex vesicle-based BBB transport modes that are important for CNS delivery of large molecules is in progress, and their BBB transport seems to be significantly affected by CNS diseases. In conclusion, today, CNS drug delivery of small drugs can be well assessed and understood by integrative approaches, although there is still quite a long way to go to understand CNS drug delivery of large molecules.

Brain Distribution of Drugs: Pharmacokinetic Considerations.

It is crucial to understand the basic principles of drug transport, from the site of delivery to the site of action within the CNS, in order to evaluate the possible utility of a new drug candidate for CNS action, or possible CNS side effects of non-CNS targeting drugs. This includes pharmacokinetic aspects of drug concentration-time profiles in plasma and brain, blood-brain barrier transport and drug distribution within the brain parenchyma as well as elimination processes from the brain. Knowledge of anatomical and physiological aspects connected with drug delivery is crucial in this context. The chapter is intended for professionals working in the field of CNS drug development and summarizes key pharmacokinetic principles and state-of-the-art experimental methodologies to assess brain drug disposition. Key parameters, describing the extent of unbound (free) drug across brain barriers, in particular blood-brain and blood-cerebrospinal fluid barriers, are presented along with their application in drug development. Special emphasis is given to brain intracellular pharmacokinetics and its role in evaluating target engagement. Fundamental neuropharmacokinetic differences between small molecular drugs and biologicals are discussed and critical knowledge gaps are outlined.

In Vivo Studies of Drug BBB Transport: Translational Challenges and the Role of Brain Imaging.

Drug delivery to the brain is challenging to study due to the complexity of the barriers of the central nervous system (CNS). The present chapter describes and compares experimental methods such as microdialysis, two-photon laser scanning fluorescence microscopy and positron emission tomography (PET) that can be used for in vivo studies of drug transport across the blood-brain barrier (BBB). The selection of appropriate method is based on the research question, and the different methods will in most cases provide complementary information. Attention is also given to the fact that the BBB might undergo changes in integrity, protein expression and other morphological alterations as a result of disease. The use of animal models of human disease is therefore also discussed. Special emphasis is given to translational aspects of the different methods and readouts.

Neuropharmacokinetic visualization of regional and subregional unbound antipsychotic drug transport across the blood-brain barrier.

Comprehensive determination of the extent of drug transport across the region-specific blood-brain barrier (BBB) is a major challenge in preclinical studies. Multiple approaches are needed to determine the regional free (unbound) drug concentration at which a drug engages with its therapeutic target. We present an approach that merges in vivo and in vitro neuropharmacokinetic investigations with mass spectrometry imaging to quantify and visualize both the extent of unbound drug BBB transport and the post-BBB cerebral distribution of drugs at regional and subregional levels. Direct imaging of the antipsychotic drugs risperidone, clozapine, and olanzapine using this approach enabled differentiation of regional and subregional BBB transport characteristics at 20-µm resolution in small brain regions, which could not be achieved by other means. Our approach allows investigation of heterogeneity in BBB transport and presents new possibilities for molecular psychiatrists by facilitating interpretation of regional target-site exposure results and decision-making.

Perspectives on Nanodelivery to the Brain: Prerequisites for Successful Brain Treatment.

Nanocarriers (NCs) are promising tools to improve drug delivery across the blood-brain barrier (BBB) for more effective treatment of brain disorders, although there is a scarcity of clinical translation of brain-directed NCs. In order to drive the development of brain-oriented NCs toward clinical success, it is essential to understand the prerequisites for nanodelivery to be successful in brain treatment. In this Perspective, we present how pharmacokinetic/pharmacodynamic (PK/PD), formulation and nanotoxicity factors impact the therapeutic success of brain-specific nanodelivery. Properties including high loading efficiency, slow in vivo drug release, long systemic circulation, an increase in unbound brain-to-plasma concentration/exposure ratio (Kp,uu,brain), high drug potency, and minimal nanotoxicity are prerequisites that should preferably be combined to maximize the therapeutic potential of a brain-targeted NC. The PK of brain-directed NCs needs to be evaluated in a more therapeutically relevant manner, focusing on the released, unbound drug. It is more crucial to increase the Kp,uu,brain than to improve the ability of the NC to cross the BBB in its intact form. Brain-targeted NCs, which are mostly developed for treating brain tumors, including metastases, should aim to enhance drug delivery not just to tumor regions with disrupted BBB, but equally important to regions with intact BBB where the drugs themselves have problems reaching. This article provides critical insights into how a brain-targeted nanoformulation needs to be designed and optimized to achieve therapeutic success in the brain.

A Cross-Sectional Study Assessing Appropriateness Of Inhaled Corticosteroid Treatment In Primary And Secondary Care Patients With COPD In Sweden.

Purpose: Inhaled corticosteroids (ICS) are often more widely prescribed in the treatment of chronic obstructive pulmonary disease (COPD) than what is recommended in the guidelines. The aim of this study was to evaluate the appropriateness of ICS treatment in COPD patients using the algorithm proposed by the International Primary Care Respiratory Group (IPCRG) and to identify factors associated with ICS treatment. Patients and methods: Appropriateness of ICS therapy was studied with respect to concomitant asthma, history of exacerbations and blood eosinophils (B-Eos) in a Swedish cohort of primary and secondary care patients with COPD. Factors associated with ICS were investigated using multivariable logistic regression. Results: Triple treatment was found to be the most common treatment combination, used by 46% of the 561 included patients, and in total 63% were using ICS. When applying the IPCRG algorithm, there was a possible indication for discontinuation of ICS in 55% of the patients with ICS treatment. Of the patients not using ICS, 18% had an indication for starting such treatment. The strongest factors associated with ICS therapy were frequent exacerbations (aOR 8.61, 95% CI 4.06, 20.67), secondary care contacts (aOR 6.99, 95% CI 2.48, 25.28) and very severe airflow limitation (aOR 5.91, 95% CI 1.53, 26.58). Conclusion: More than half of the COPD patients on ICS met the criteria where withdrawal of the treatment could be tried. There was, however, also a subgroup of patients not using ICS for whom there was an indication for starting ICS treatment. Patients using ICS were characterized by more frequent exacerbations and lower lung function.

Mechanistic Study on the Use of the l-Type Amino Acid Transporter 1 for Brain Intracellular Delivery of Ketoprofen via Prodrug: A Novel Approach Supporting the Development of Prodrugs for Intracellular Targets.

l-Type amino acid transporter 1 (LAT1), selectively expressed at the blood-brain barrier (BBB) and brain parenchymal cells, mediates brain delivery of drugs and prodrugs such as l-dopa and gabapentin. Although knowledge about BBB transport of LAT1-utilizing prodrugs is available, there is a lack of quantitative information about brain intracellular delivery and influence of prodrugs on the transporter's physiological state. We studied the LAT1-mediated intrabrain distribution of a recently developed prodrug of the cyclooxygenase inhibitor ketoprofen as well as its impact on transporter protein expression and function (i.e., amino acid exchange) using brain slice method in mice and rats. The intrabrain distribution of the prodrug was 16 times higher than that of ketoprofen. LAT1 involvement in brain cellular barrier uptake of the prodrug was confirmed, reflected by a higher unbound brain intracellular compared to brain extracellular fluid concentration. The prodrug did not alter LAT1 protein expression and amino acid exchange. Integration of derived parameters with previously performed in vivo pharmacokinetic study using the Combinatory Mapping Approach allowed to estimate the brain extra- and intracellular levels of unbound ketoprofen, prodrug, and released parent drug. The overall efficiency of plasma to brain intracellular delivery of prodrug-released ketoprofen was 11 times higher than after ketoprofen dosing. In summary, this study provides quantitative information supporting the use of the LAT1-mediated prodrug approach for enhanced brain delivery of drugs with intracellular targets.

Understanding the Influence of Nanocarrier-Mediated Brain Delivery on Therapeutic Performance Through Pharmacokinetic-Pharmacodynamic Modeling.

This study aimed at evaluating how encapsulation in a regular nanocarrier (NC) (providing extended circulation time) or in a brain-targeting NC (providing prolonged circulation time and increased brain uptake) may influence the therapeutic index compared with the unformulated drug and to explore the key parameters affecting therapeutic performance using a model-based approach. Pharmacokinetic (PK) models were built with chosen PK parameters. For a scenario where central effect depends on area under the unbound brain concentration curve and peripheral toxicity relates to peak unbound plasma concentration, dose-effect and drug-side effect curves were constructed, and the therapeutic index was evaluated. Regular NC improved the therapeutic index compared with the unformulated drug due to reduced peripheral toxicity, while brain-targeting NC enhanced the therapeutic index by lowering peripheral toxicity and increasing central effect. Decreasing drug release rate or systemic clearance of NC with drug still encapsulated could increase the therapeutic index. Also, a drug with shorter half-life would therapeutically benefit more from a NC encapsulation. This work provides insights into how a NC for brain delivery should be optimized to maximize the therapeutic performance and is helpful to predict if and to what extent a drug with certain PK properties would obtain therapeutic benefit from nanoencapsulation.

Targeted brain delivery of methotrexate by glutathione PEGylated liposomes: How can the formulation make a difference?

The purpose of this study was to quantitatively investigate how conjugation of GSH to different liposomal formulations influence the brain delivery of methotrexate (MTX) in rats. GSH-PEG liposomal MTX based on hydrogenated soy phosphatidylcholine (HSPC) or egg yolk phosphatidylcholine (EYPC) and their corresponding PEG control liposomes were prepared. The brain delivery of MTX after intravenously administering free MTX, four liposomal formulations or free MTX + empty GSH-PEG-HSPC liposomes was evaluated by performing microdialysis in brain interstitial fluid and blood. Compared to free MTX with a steady-state unbound brain-to-plasma concentration ratio (Kp,uu) of 0.10, PEG-HSPC liposomes did not affect the brain uptake of MTX, while PEG-EYPC liposomes improved the uptake (Kp,uu 1.5, p < 0.05). Compared to PEG control formulations, GSH-PEG-HSPC liposomes increased brain delivery of MTX by 4-fold (Kp,uu 0.82, p < 0.05), while GSH-coating on PEG-EYPC liposomes did not result in a further enhancement in uptake. The co-administration of empty GSH-PEG-HSPC liposomes with free MTX did not influence the uptake of MTX into the brain. This work showed that the brain-targeting effect of GSH-PEG liposomal MTX is highly dependent on the liposomal formulation that is combined with GSH, providing insights on formulation optimization of this promising brain delivery platform.

Heterogeneous drug tissue binding in brain regions of rats, Alzheimer's patients and controls: impact on translational drug development.

For preclinical and clinical assessment of therapeutically relevant unbound, free, brain concentrations, the pharmacokinetic parameter fraction of unbound drug in brain (fu,brain) is commonly used to compensate total drug concentrations for nonspecific brain tissue binding (BTB). As, homogenous BTB is assumed between species and in health and disease, rat BTB is routinely used. The impact of Alzheimer's disease (AD) on drug BTB in brain regions of interest (ROI), i.e., fu,brain,ROI, is yet unclear. This study for the first time provides insight into regional drug BTB and the validity of employing rat fu,brain,ROI as a surrogate of human BTB, by investigating five marketed drugs in post-mortem tissue from AD patients (n = 6) and age-matched controls (n = 6). Heterogeneous drug BTB was observed in all within group comparisons independent of disease and species. The findings oppose the assumption of uniform BTB, highlighting the need of case-by-case evaluation of fu,brain,ROI in translational CNS research.

Rate and extent of mitragynine and 7-hydroxymitragynine blood-brain barrier transport and their intra-brain distribution: the missing link in pharmacodynamic studies.

Mitragyna speciosa is reported to be beneficial for the management of chronic pain and opioid withdrawal in the evolving opioid epidemic. Data on the blood-brain barrier (BBB) transport of mitragynine and 7-hydroxymitragynine, the active compounds of the plant, are still lacking and inconclusive. Here, we present for the first time the rate and the extent of mitragynine and 7-hydroxymitragynine transport across the BBB, with an investigation of their post-BBB intra-brain distribution. We utilized an in vitro BBB model to study the rate of BBB permeation of the compounds and their interaction with efflux transporter P-glycoprotein (P-gp). Mitragynine showed higher apical-to-basolateral (A-B, i.e. blood-to-brain side) permeability than 7-hydroxymitragynine. 7-Hydroxymitragynine showed a tendency to efflux, with efflux ratio (B-A/A-B) of 1.39. Both were found to inhibit the P-gp and are also subject to efflux by the P-gp. Assessment of the extent of BBB transport in vivo in rats from unbound brain to plasma concentration ratios (Kp,uu,brain ) revealed extensive efflux of both compounds, with less than 10 percent of unbound mitragynine and 7-hydroxymitragynine in plasma crossing the BBB. By contrast, the extent of intra-brain distribution was significantly different, with mitragynine having 18-fold higher brain tissue uptake in brain slice assay compared with 7-hydroxymitragynine. Mitragynine showed a moderate capacity to accumulate inside brain parenchymal cells, while 7-hydroxymitragynine showed restricted cellular barrier transport. The presented findings from this systematic investigation of brain pharmacokinetics of mitragynine and 7-hydroxymitragynine are essential for design and interpretation of in vivo experiments aiming to establish exposure-response relationship.

In Vivo Quantitative Understanding of PEGylated Liposome's Influence on Brain Delivery of Diphenhydramine.

Despite the promising features of liposomes as brain drug delivery vehicles, it remains uncertain how they influence the brain uptake in vivo. In order to gain a better fundamental understanding of the interaction between liposomes and the blood-brain barrier (BBB), it is indispensable to test if liposomes affect drugs with different BBB transport properties (active influx or efflux) differently. The aim of this study was to quantitatively evaluate how PEGylated (PEG) liposomes influence brain delivery of diphenhydramine (DPH), a drug with active influx at the BBB, in rats. The brain uptake of DPH after 30 min intravenous infusion of free DPH, PEG liposomal DPH, or free DPH + empty PEG liposomes was compared by determining the unbound DPH concentrations in brain interstitial fluid and plasma with microdialysis. Regular blood samples were taken to measure total DPH concentrations in plasma. Free DPH was actively taken up into the brain time-dependently, with higher uptake at early time points followed by an unbound brain-to-plasma exposure ratio ( Kp,uu) of 3.0. The encapsulation in PEG liposomes significantly decreased brain uptake of DPH, with a reduction of Kp,uu to 1.5 ( p < 0.05). When empty PEG liposomes were coadministered with free drug, DPH brain uptake had a tendency to decrease ( Kp,uu 2.3), and DPH was found to bind to the liposomes. This study showed that PEG liposomes decreased the brain delivery of DPH in a complex manner, contributing to the understanding of the intricate interactions between drug, liposomes, and the BBB.

Blood-brain barrier integrity in a mouse model of Alzheimer's disease with or without acute 3D6 immunotherapy.

The blood-brain barrier (BBB) is suggested to be compromised in Alzheimer's disease (AD). The concomitant presence of vascular amyloid beta (Aß) pathology, so called cerebral amyloid angiopathy (CAA), also predisposes impairment of vessel integrity. Additionally, immunotherapy against Aß may lead to further damage of the BBB. To what extent this affects the BBB passage of molecules is debated. The current study aimed to investigate BBB integrity to large molecules in transgenic mice displaying abundant Aß pathology and age matched wild type animals, with or without acute anti-Aß antibody treatment. Animals were administered a single i.v. injection of PBS or 3D6 (10 mg/kg), i.e. the murine version of the clinically investigated Aß antibody bapineuzumab, supplemented with [125I]3D6. Three days post injections, a 4 kDa FITC and a 150 kDa Antonia Red dextran were administered i.v. to all animals. After termination, fluorescent detection in brain and serum was used for the calculation of dextran brain-to-blood concentration ratios. Further characterization of antibody fate and the presence of CAA were investigated using radioactivity measurements and Congo red staining. BBB passage of large molecules was equally low in wild type and transgenic mice, suggesting an intact BBB despite Aß pathology. Neither was the BBB integrity affected by acute 3D6 treatment. However, CAA was confirmed in the transgenes and local antibody accumulations were observed in the brain, indicating CAA-antibody interactions. The current study shows that independently of Aß pathology or acute 3D6 treatment, the BBB is intact, without extensive permeability to large molecules, including the 3D6 antibody.

Rate of small-molecular drug transport across the blood-brain barrier in a pericyte-deficient state.

Close interactions between pericytes and brain endothelial cells are essential for keeping the blood-brain barrier (BBB) functional and to restrict the transport of various xenobiotics from blood circulation to the brain parenchyma. Profound understanding of pericyte roles at the BBB and underlying mechanisms for the regulation of BBB transport are important as a potential strategy to improve drug delivery in treatment of CNS disorders. The aim of the present study was to investigate pericyte role in the rate of small-molecular drug transport across the BBB, by examining three model compounds in a pericyte-deficient state. Diazepam, oxycodone and paliperidone were selected for this purpose based on utilization of different transport mechanisms at the BBB. The rate of brain uptake was assessed by implementing the trans-cardiac in situ brain perfusion technique. Radiolabeled 14C-sucrose was used as a vascular marker. Pericyte-deficient mice (Pdgfbret/ret) exhibited significantly larger brain vascular volumes (Vvasc) 1.72 ±â€¯0.13 mL/100 g brain, compared to littermate controls with normal pericyte coverage (Pdgfbret/+) 1.15 ±â€¯0.13 mL/100 g brain (p < 0001). However, the unidirectional transfer coefficient Kin, which describes the rate of brain uptake, was not different between Pdgfbret/ret and Pdgfbret/+ mice for all three tested compounds. Taken together the present results indicate no pericyte influence in the rate of small-molecular drug transport at the BBB, despite the larger brain vascular volumes that were observed in a pericyte-deficient state.

Pharmacokinetics of pericyte involvement in small-molecular drug transport across the blood-brain barrier.

Pericytes are perivascular cells that play important roles in the regulation of the blood-brain barrier (BBB) properties. Pericyte-deficiency causes compromised BBB integrity and increase in permeability to different macromolecules mainly by upregulated transcytosis. The aim of the present study was to investigate pericyte involvement in the extent of small-molecular drug transport across the BBB. This was performed with five compounds: diazepam, digoxin, levofloxacin, oxycodone and paliperidone. Compounds were administered at low doses via subcutaneous injections as a cassette (simultaneously) to pericyte-deficient Pdgfbret/ret mice and corresponding WT controls. Total drug partitioning across the BBB was calculated as the ratio of total drug exposures in brain tissue and plasma (Kp,brain). In addition, equilibrium dialysis experiments were performed to estimate unbound drug fractions in brain (fu,brain) and plasma (fu,plasma). This enabled estimation of unbound drug partitioning coefficients (Kp,uu,brain). The results indicated slight tendencies towards increase of total brain exposures in Pdgfbret/ret mice as reflected in Kp,brain values, which were within the 2-fold limit. Part of these differences could be explained by differences in plasma protein binding. No difference was found in brain tissue binding. The combined in vivo and in vitro data resulted in no differences in BBB transport in pericyte-deficiency, as described by similar Kp,uu,brain values in Pdgfbret/ret and control mice. In conclusion, these findings imply no influence of pericytes on the extent of BBB transport of small-molecular drugs, and suggest preserved BBB features relevant for handling of this type of molecules irrespective of pericyte presence at the brain endothelium.

Correction to: Current research into brain barriers and the delivery of therapeutics for neurological diseases: a report on CNS barrier congress London, UK, 2017.

After publication of the article [1], it has been brought to our attention that there are some errors in the formatting of names in the final version of the article.

Intact blood-brain barrier transport of small molecular drugs in animal models of amyloid beta and alpha-synuclein pathology.

Pathophysiological impairment of the neurovascular unit, including the integrity and dynamics of the blood-brain barrier (BBB), has been denoted both a cause and consequence of neurodegenerative diseases. Pathological impact on BBB drug delivery has also been debated. The aim of the present study was to investigate BBB drug transport, by determining the unbound brain-to-plasma concentration ratio (Kp,uu,brain), in aged AßPP-transgenic mice, α-synuclein transgenic mice, and wild type mice. Mice were dosed with a cassette of five compounds, including digoxin, levofloxacin (1 mg/kg, s.c.), paliperidone, oxycodone, and diazepam (0.25 mg/kg, s.c.). Brain and blood were collected at 0.5, 1, or 3 h after dosage. Drug concentrations were measured using LC-MS/MS. The total brain-to-plasma concentration ratio was calculated and equilibrium dialysis was used to determine the fraction of unbound drug in brain and plasma for all compounds. Together, these three measures were used to determine the Kp,uu,brain value. Despite Aß or α-synuclein pathology in the current animal models, no difference was observed in the extent of drug transport across the BBB compared to wild type animals for any of the compounds investigated. Hence, the present study shows that the concept of a leaking barrier within neurodegenerative conditions has to be interpreted with caution when estimating drug transport into the brain. The capability of the highly dynamic BBB to regulate brain drug exposure still seems to be intact despite the presence of pathology.