Left-Right Difference in Brain Pharmacokinetics Following Nasal Administration Via One-Site Nostrils.

The olfactory and trigeminal pathways are direct delivery pathways between the nose and brain. To determine the effect of direct delivery on drug distribution in the brain, two model drugs with different physical properties, antipyrine (ANP), with high membrane permeability, and ranitidine (RNT), with low membrane permeability, were selected. For ANP, direct delivery from the nose to the brain was observed only in the olfactory bulb beside the nasal cavity, with a direct transport percentage (DTP) of approximately 45 %, whereas in the frontal and occipital brains, the contribution from the systemic circulation to the brain was observed as the primary route of brain distribution. No significant variations were observed in the pharmacokinetics of ANP in the left and right brain, whereas RNT was distributed in all brain regions with a DTP of > 95 %. The closer the brain region is to the nasal cavity, the higher the DTP. Furthermore, the left brain, the same nostril site (left nostril) of administration, had a larger level of drug delivery than the right brain. These findings imply that the influence of the administered nostril site differs based on the physicochemical properties and amount of the drug.

Investigation of Antibody Pharmacokinetics in the Brain Following Intra-CNS Administration and Development of PBPK Model to Characterize the Data.

Despite the promising potential of direct central nervous system (CNS) antibody administration to enhance brain exposure, there remains a significant gap in understanding the disposition of antibodies following different intra-CNS injection routes. To bridge this knowledge gap, this study quantitatively investigated the brain pharmacokinetics (PK) of antibodies following intra-CNS administration. The microdialysis samples from the striatum (ST), cerebrospinal fluid (CSF) samples through cisterna magna (CM) puncture, plasma, and brain homogenate samples were collected to characterize the pharmacokinetics (PK) profiles of a non-targeting antibody, trastuzumab, following intracerebroventricular (ICV), intracisternal (ICM), and intrastriatal (IST) administration. For a comprehensive analysis, these intra-CNS injection datasets were juxtaposed against our previously acquired intravenous (IV) injection data obtained under analogous experimental conditions. Our findings highlighted that direct CSF injections, either through ICV or ICM, resulted in ~ 5-6-fold higher interstitial fluid (ISF) drug exposure than IV administration. Additionally, the low bioavailability observed following IST administration indicates the existence of a local degradation process for antibody elimination in the brain ISF along with the ISF bulk flow. The study further refined a physiologically based pharmacokinetic (PBPK) model based on new observations by adding the perivascular compartments, oscillated CSF flow, and the nonspecific uptake and degradation of antibodies by brain parenchymal cells. The updated model can well characterize the antibody PK following systemic and intra-CNS administration. Thus, our research offers quantitative insight into antibody brain disposition pathways and paves the way for determining optimal dosing and administration strategies for antibodies targeting CNS disorders.

Donepezil Brain and Blood Pharmacokinetic Modeling after Nasal Film and Oral Solution Administration in Mice.

Intranasal delivery is a non-invasive mode of administration, gaining popularity due to its potential for targeted delivery to the brain. The anatomic connection of the nasal cavity with the central nervous system (CNS) is based on two nerves: olfactory and trigeminal. Moreover, the high vasculature of the respiratory area enables systemic absorption avoiding possible hepatic metabolism. Due to these physiological peculiarities of the nasal cavity, compartmental modeling for nasal formulation is considered a demanding process. For this purpose, intravenous models have been proposed, based on the fast absorption from the olfactory nerve. However, most of the sophisticated approaches are required to describe the different absorption events occurring in the nasal cavity. Donepezil was recently formulated in the form of nasal film ensuring drug delivery in both bloodstream and the brain. In this work, a three-compartment model was first developed to describe donepezil oral brain and blood pharmacokinetics. Subsequently, using parameters estimated by this model, an intranasal model was developed dividing the administered dose into three fractions, corresponding to absorption directly to the bloodstream and brain, as well as indirectly to the brain expressed through transit compartments. Hence, the models of this study aim to describe the drug flow on both occasions and quantify the direct nose-to-brain and systemic distribution.

Amoxapine-Loaded Solid Lipid Nanoparticles with Superior Preclinical Pharmacokinetics for Better Brain Delivery: LC-MS/MS and GC-MS Analysis.

The tricyclic antidepressant amoxapine (AMX) has been reported for a rapid onset of action compared to other cyclic antidepressants. It has very low solubility and bioavailability due to first-pass metabolism. Therefore, we planned to develop solid lipid nanoparticles (SLNs) of AMX using a single emulsification method to increase its solubility and bioavailability. HPLC and LC-MS/MS methods were developed further to quantify AMX in the formulation, plasma, and brain tissue samples. The formulation was studied for entrapment efficiency, loading, and in vitro drug release. Particle size and ζ potential analyses, AFM, SEM, TEM, DSC, and XRD were used for further characterization. In vivo oral pharmacokinetic and brain pharmacokinetic studies were performed using Wistar rats. The entrapment and loading efficiencies of AMX in SLNs were 85.8 ± 3.42 and 4.5 ± 0.45%, respectively. The developed formulation had a mean particle size of 151.5 ± 7.02 nm and a polydispersity index of 0.40 ± 0.11. DSC and XRD results indicated that AMX was incorporated into the nanocarrier system in an amorphous form. SEM, TEM, and AFM studies of AMX-SLNs confirmed the particles' spherical shape and nanoscale size. AMX solubility increased by approx. 2.67 times compared to the pure drug. The developed LC-MS/MS method was successfully applied to the oral and brain pharmacokinetic study of AMX-loaded SLNs in rats. Oral bioavailability was enhanced 1.6 times compared to the pure drug. The peak plasma concentrations of pure AMX and AMX-SLNs were 617.4 ± 137.4 and 1043.5 ± 150.2 (ng/mL), respectively. AMX-SLNs showed more than 5.8 times brain concentration compared to the pure drug. Based on the findings, it appears that utilizing a solid lipid nanoparticle carrier to transport AMX can be a highly effective delivery method with improved pharmacokinetic properties in the brain. This approach may prove valuable for future antidepressant treatment.

Study on the opening effect of eucalyptol on the blood-brain barrier and its brain pharmacokinetics.

Eucalyptol, a natural epoxide monoterpene, was found in rat brain tissue after oral administration in our previous study, suggesting that the compound may possess the ability to pass the blood-brain barrier (BBB). However, a few studies have demonstrated that eucalyptol does penetrate the BBB. The aims of this study were to determine the opening effect of eucalyptol on the BBB in rats, to establish and validate a method for the determination of eucalyptol in brain tissue, and to reveal its brain pharmacokinetic characteristics. The opening effect of BBB was assessed by dye extravasation and ultrastructural alterations, and the quantitative method of eucalyptol in rat brain tissue was established and confirmed. For pharmacokinetic research, rat brain samples were taken at 0.05, 0.167, 0.5, 1, 2.5, 5, 10, and 15 h after administration. There was a significantly higher extravasation of Evans blue from the brain parenchyma of rats in the medium-dose eucalyptol group (P < 0.01), which was associated with the BBB's altered ultrastructure. It is suggested that eucalyptol increased the permeability of the BBB. After oral administration, eucalyptol was quickly absorbed by the brain. This study provides valuable information on eucalyptol use to treat illnesses of the central nervous system.

Brain regional pharmacokinetics of hydroxytyrosol and its molecular mechanism against depression assessed by multi-omics approaches.

BACKGROUND: Hydroxytyrosol (HT), as the main compound in olive leaves with its potential ability to cross blood-brain barrier (BBB), has exhibited the advantaged antidepressant effect. However, no information is available regarding the brain regional uptake of HT, as well the underlying antidepressant mechanism remains unclear. PURPOSE: To comprehensively reveal the brain uptake of HT and its specific mechanism on the accompanying antidepressant activity. STUDY DESIGN AND METHODS: The BBB penetration and brain regional distribution of HT in the normal and chronic unpredictable mild stress (CUMS)-induced depressive mice in consideration with the BBB integrality were analyzed. Then, the hippocampal region-specific responses of biomolecules and concurrent alterations in the therapeutic effect of HT on depression were explored using untargeted metabolomics, spatial-resolved metabolomics and tissue proteomics, which were confirmed by LPS-induced BV-2 microglia and CUMS mice. RESULTS: BBB permeability analysis in normal and CUMS mice confirmed that increased BBB permeability of CUMS mice was induced by the deficiency of tight junction-related proteins. Consistently, according to the established LC-MS/MS method, it was found that HT could not be largely detected in the cerebrospinal fluids and brains of normal mice after oral administration, while it could excessively penetrate the BBB (200-fold higher), and mostly distributed in the hippocampus of CUMS mice. Meanwhile, multi-omics analysis combined with targeted analysis discovered that HT could mainly improve fatty acid biosynthesis and metabolism in the hippocampus with region-specific responses and accompanying inhibition of C3-CD11b pathway in CUMS mice. Besides, in vitro experiments further confirmed the anti-complement ability of HT, which could inhibit C3-CD11b pathway for alleviating the LPS-induced BV-2 microglia activation. CONCLUSION: HT can excessively penetrate the BBB and be mostly distributed in the hippocampus of depressive mice, which contribute to improve fatty acid biosynthesis and metabolism in the hippocampus with region-specific responses and accompanying inhibition of C3-CD11b pathway for microglia activation. These findings give the clearer understanding of brain regional pharmacokinetics of HT and its accompanying molecular mechanism against depression.

Comparative study on brain pharmacokinetics of Buyang Huanwu Decoction in normal and cerebral ischemia rats using brain microdialysis combined with LC-MS/MS.

Objective: To conduct a comparative study on the brain pharmacokinetics of seven ingredients (i. e. senkyunolide A, ferulic acid, formononetin, calycosin, ononin, calycosin-O-ß-D-glucopyranoside, and paeoniflorin), which were the compounds of Buyang Huanwu Decoction (BHD), in normal and cerebral ischemia rats administrated intragastrically with BHD. Methods: The samples of normal and permanent middle cerebral artery occlusion (pMCAO) rats were collected by using brain microdialysis technique. The concentrations of seven ingredients were determined by the HPLC-MS/MS method. After the BHD were administrated intragastrically to the rats for seven consecutive days, brain microdialysis probes were inserted into the hippocampus of rats, and then the brain microdialysates were collected at 20 min time intervals for 5 h. The separation of the seven ingredients and internal standard (IS) was carried out on an ACQUITY UPLC BEH C18 (2.1 mm × 100 mm, 1.7 µm) chromatographic column, using a mobile phase consisting of acetonitrile (containing 0.1% formic acid) and water (containing 0.1% formic acid) for gradient elution within 13 min. The ionization was conducted using an ESI source in positive ion mode. Multiple reaction monitoring mode was used for quantification of ingredients in BHD. Results: Linearity, accuracy, precision, matrix effect and stability of LC-MS/MS method were all satisfactory, successfully applied to compare the pharmacokinetics of the analytes between normal and model rats after intragastric administration of BHD. Compared with the normal group, the model group after the administration of the BHD showed that T 1/2 of formononetin and ononin were longer, and except for calycosin-O-ß-D-glucopyranoside (P < 0.01), there was no significant difference between the normal group and the model group. The C max of senkyunolide A and calycosin of model group were increased, while the T max of senkyunolide A was decreased, and except for the T max of PF, the differences between the two groups were statistically significant (P < 0.01). Conclusion: The LC-MS/MS method combined with microdialysis was successfully applied to the comparative study of brain pharmacokinetics of seven ingredients in BHD. After intragastric administration of BHD, there were differences in the pharmacokinetics of seven ingredients in the brain hippocampus between normal rats and model rats, probably related to the characteristics of the ingredients and the effects of cerebral ischemia on the absorption and distribution of the ingredients.

PBPK model for antibody disposition in mouse brain: validation using large-pore microdialysis data.

The objective of this manuscript was to validate a physiologically-based pharmacokinetic (PBPK) model developed to characterize brain pharmacokinetics (PK) of monoclonal antibodies (mAbs) using novel large-pore microdialysis data generated in mice. To support this objective, brain, CSF, and ISF PK of a human anti-tetanus toxin (TeTx) antibody was measured in mice following intraperitoneal (IP) administration. This antibody has no binding in mice. In addition, our recently published mouse brain PK data generated following intravenous (IV) and IP administration of trastuzumab in mice, and other published PK data for brain disposition of antibody in mice, were used to evaluate the PBPK model. All the model parameters were obtained from literature or kept the same as in our previously published manuscript. The revised PBPK model was able to characterize the PK of antibodies in mice brain, CSF, and ISF reasonably well (i.e., within a three-fold error). However, a priori selected parameters led to underprediction of ISF PK during the initial phase of the profile. A local sensitivity analysis suggested that minor changes in several brain-related parameters can help overcome this discrepancy, where an increase in the convective flow of antibodies across BBB was found to be the most parsimonious way to capture all the PK profiles well. However, the presence of this pathway needs further validation. As such, here we have presented an improved PBPK model to characterize and predict the PK of mAbs in different regions of the mouse brain following systemic administration. This model can serve as a quantitative tool to facilitate the discovery, preclinical evaluation, and preclinical-to-clinical translation of novel antibodies targeted against CNS disorders.

Brain regional pharmacokinetics following the oral administration of curcumagalactomannosides and its relation to cognitive function.

OBJECTIVE: Though a number of bioavailable formulations of curcuminoids have been reported and available commercially as nutraceuticals for brain health, systematic informations on their blood-brain-barrier permeability and brain tissue distribution have not been reported. The present study was aimed to investigate the brain regional pharmacokinetics of curcuminoids following both single dose and repeated dose oral administration of a self-emulsifying food-grade formulation of curcuminoids using fenugreek galactomannan hydrogel scaffold as 'curcumagalactomannosides' (CGM), and its influence on cognitive functions in comparison with unformulated natural curcuminoids (NC) in Wistar rats. METHODS: CGM was given to animals in single dose (100 mg curcuminoids/kg b. wt.) and repeated dose (100 mg curcuminoids/kg b. wt. for 28 days) and the concentration of total curcuminoids at various parts of brain was evaluated at different time points using Ultra-performance liquid chromatography/electrospray ionization triple quadruple tandem mass spectroscopy (UPLC-ESI-MS/MS) system. Another set of animals were also fed with CGM at single dose (100 mg curcuminoids/kg b. wt.) and repeated dose (100 mg curcuminoids/kg b. wt. for 28 days) and the behavioural studies were conducted using open field test and radial arm maze. RESULTS: UPLC-ESI-MS/MS analyses of plasma revealed significant absorption of unconjugated (free) curcuminoids upon both single and repeated dose administration of CGM with maximum concentrations of 173.34 ± 27.12 ng/mL and 223.22 ± 32.73 ng/mL, respectively. Further analysis of brain tissues demonstrated significant blood-brain-barrier permeability. Brain regional pharmacokinetics (AUC, Cmax and t1/2) indicated a relative distribution order of hippocampus > striatum > cerebellum > cerebral cortex > brain stem. Supplementation of CGM for 28 days also offered significant (p < 0.05) improvement in locomotor activity and reduction in spatial memory errors as compared to NC. The NC treatment also improved the behaviour better than the vehicle-treated group. CONCLUSION: CGM could distribute significant amount of free curcuminoids, in brain especially in the hippocampus at both single and repeated dose administration with an elimination half-life of 2.6 h. CGM also showed a positive impact in behaviour of animals in comparison with normal unformulated curcuminoids.

Comparative study on brain pharmacokinetics of Buyang Huanwu Decoction in normal and cerebral ischemia rats using brain microdialysis combined with LC-MS/MS / 中草药·英文版

Objective: To conduct a comparative study on the brain pharmacokinetics of seven ingredients (i. e. senkyunolide A, ferulic acid, formononetin, calycosin, ononin, calycosin-O-β-D-glucopyranoside, and paeoniflorin), which were the compounds of Buyang Huanwu Decoction (BHD), in normal and cerebral ischemia rats administrated intragastrically with BHD. Methods: The samples of normal and permanent middle cerebral artery occlusion (pMCAO) rats were collected by using brain microdialysis technique. The concentrations of seven ingredients were determined by the HPLC-MS/MS method. After the BHD were administrated intragastrically to the rats for seven consecutive days, brain microdialysis probes were inserted into the hippocampus of rats, and then the brain microdialysates were collected at 20 min time intervals for 5 h. The separation of the seven ingredients and internal standard (IS) was carried out on an ACQUITY UPLC BEH C

Brain pharmacokinetics of two BBB penetrating bispecific antibodies of different size.

BACKGROUND: Transferrin receptor (TfR1) mediated enhanced brain delivery of antibodies have been studied extensively in preclinical settings. However, the brain pharmacokinetics, i.e. brain entry, distribution and elimination are still not fully understood for this class of antibodies. The overall aim of the study was to compare the brain pharmacokinetics of two BBB-penetrating bispecific antibodies of different size (210 vs 58 kDa). Specifically, we wanted to investigate if the faster systemic clearance of the smaller non-IgG antibody di-scFv3D6-8D3, in comparison with the IgG-based bispecific antibody mAb3D6-scFv8D3, was also reflected in the brain. METHODS: Wild-type (C57/Bl6) mice were injected with 125I-iodinated ([125I]) mAb3D6-scFv8D3 (n = 46) or [125I]di-scFv3D6-8D3 (n = 32) and euthanized 2, 4, 6, 8, 10, 12, 16, or 24 h post injection. Ex vivo radioactivity in whole blood, peripheral organs and brain was measured by γ-counting. Ex vivo autoradiography and nuclear track emulsion were performed on brain sections to investigate brain and parenchymal distribution. Capillary depletion was carried out at 2, 6, and 24 h after injection of [125I]mAb3D6-scFv8D3 (n = 12) or [125I]di-scFv3D6-8D3 (n = 12), to estimate the relative levels of radiolabelled antibody in brain capillaries versus brain parenchyma. In vitro binding kinetics for [125I]mAb3D6-scFv8D3 or [125I]di-scFv3D6-8D3 to murine TfR were determined by LigandTracer. RESULTS: [125I]di-scFv3D6-8D3 showed faster elimination from blood, lower brain Cmax, and Tmax, a larger parenchymal-to-capillary concentration ratio, and a net elimination from brain at an earlier time point after injection compared with the larger [125I]mAb3D6-scFv8D3. However, the elimination rate from brain did not differ between the antibodies. The study also indicated that [125I]di-scFv3D6-8D3 displayed lower avidity than [125I]mAb3D6-scFv8D3 towards TfR1 in vitro and potentially in vivo, at least at the BBB. CONCLUSION: A smaller size and lower TfR1 avidity are likely important for fast parenchymal delivery, while elimination of brain-associated bispecific antibodies may not be dependent on these characteristics.

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

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.

Brain pharmacokinetics of anti-transferrin receptor antibody affinity variants in rats determined using microdialysis.

Receptor-mediated transcytosis (RMT) is used to enhance the delivery of monoclonal antibodies (mAb) into the central nervous system (CNS). While the binding to endogenous receptors on the brain capillary endothelial cells (BCECs) may facilitate the uptake of mAbs in the brain, a strong affinity for the receptor may hinder the efficiency of transcytosis. To quantitatively investigate the effect of binding affinity on the pharmacokinetics (PK) of anti-transferrin receptor (TfR) mAbs in different regions of the rat brain, we conducted a microdialysis study to directly measure the concentration of free mAbs at different sites of interest. Our results confirmed that bivalent anti-TfR mAb with an optimal dissociation constant (KD) value (76 nM) among four affinity variants can have up to 10-fold higher transcytosed free mAb exposure in the brain interstitial fluid (bISF) compared to lower and higher affinity mAbs (5 and 174 nM). This bell-shaped relationship between KD values and the increased brain exposure of mAbs was also visible when using whole-brain PK data. However, we found that mAb concentrations in postvascular brain supernatant (obtained after capillary depletion) were almost always higher than the concentrations measured in bISF using microdialysis. We also observed that the increase in mAb area under the concentration curve in CSF compartments was less significant, which highlights the challenge in using CSF measurement as a surrogate for estimating the efficiency of RMT delivery. Our results also suggest that the determination of mAb concentrations in the brain using microdialysis may be necessary to accurately measure the PK of CNS-targeted antibodies at the site-of-actions in the brain.

Antipsychotic Potential and Safety Profile of TPGS-Based Mucoadhesive Aripiprazole Nanoemulsion: Development and Optimization for Nose-To-Brain Delivery.

Delivering therapeutics to the brain using conventional dosage forms is always a challenge, thus the present study was aimed to formulate mucoadhesive nanoemulsion (MNE) of aripiprazole (ARP) for intranasal delivery to transport the drug directly to the brain. Therefore, a TPGS based ARP-MNE was formulated and optimized using the Box-Behnken statistical design. The improved in vitro release profile of the formulation was in agreement to enhanced ex vivo permeation through sheep mucous membranes with a maximum rate of permeation co-efficient (62.87  cm h-1 × 103) and flux (31.43  µg cm-2.h-1). The pharmacokinetic profile following single-dose administration showed the maximum concentration of drug in the brain (Cmax) of 15.19 ± 2.51  µg mL-1 and Tmax of 1 h in animals with ARP-MNE as compared to 10.57 ± 1.88  µg mL-1 and 1 h, and 2.52 ± 0.38  µg mL-1 and 3 h upon intranasal and intravenous administration of ARP-NE, respectively. Further, higher values of % drug targeting efficiency (96.9%) and % drug targeting potential (89.73%) of ARP-MNE through intranasal administration were investigated. The studies in Wistar rats showed no existence of extrapyramidal symptoms through the catalepsy test and forelimb retraction results. No ex vivo ciliotoxicity on nasal mucosa reflects the safety of the components and delivery tool. Further, findings on locomotor activity and hind-limb retraction test in ARP-MNE treated animals established its antipsychotic efficacy. Thus, it can be inferred that the developed ARP-MNE could effectively be explored as brain delivery cargo in the effective treatment of schizophrenia without producing any toxic manifestation.

Brain pharmacokinetics and biodistribution of 11C-labeled isoproterenol in rodents.

INTRODUCTION: Isoproterenol is a non-selective ß receptor agonist, which is a drug approved for bradycardia and bronchial asthma in many countries. Recently, isoproterenol has been reported to have the potential as a drug for the treatment of Alzheimer's disease by inhibiting the aggregation of tau protein. Isoproterenol is a highly potent drug causing increases in heart rates even when its plasma concentration is very low. Thus, it is critical to know if potentially effective therapeutic levels of isoproterenol can be achieved, maintaining safe plasma levels without any untoward pharmacological effects. The purpose of the study is to investigate the brain pharmacokinetics and biodistribution of 11C-labeled isoproterenol in rodents. METHODS: We performed positron emission tomography (PET) brain imaging and biodistribution studies of [11C]isoproterenol. 120-min scans with arterial blood sampling were performed in rats. Additionally, plasma and brain homogenates were analyzed with radio-HPLC to characterize its metabolite profiles. As a measure of [11C]isoproterenol brain uptake, total distribution volumes were determined by a pharmacokinetic compartment model. Biodistribution of [11C]isoproterenol was investigated in mice at six-time points from 1-min to 90-min after injection. RESULTS: We found a modest brain uptake of [11C]isoproterenol. Its brain pharmacokinetics showed that the concentration of isoproterenol in the brain at equilibrium was about two-fold higher than in the plasma (total distribution volumes 2.0 ± 0.2 cm3/mL). Only unmetabolized isoproterenol was detected in the brain at 30 min after injection, although isoproterenol was rapidly metabolized in plasma. The biodistribution study showed that isoproterenol and its metabolite are excreted mainly via the urinary system. CONCLUSIONS, ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: In this study, we have shown that rat brain concentrations of isoproterenol are only two-fold of that in plasma at equilibrium. If the brain pharmacokinetics are similar in the human brain, it may be difficult to achieve potentially therapeutic levels of this drug safely in humans. Further studies appear warranted to investigate the brain pharmacokinetics in humans with PET using [11C]isoproterenol.

Developmental patterns in human blood-brain barrier and blood-cerebrospinal fluid barrier ABC drug transporter expression.

When drugs exert their effects in the brain, linear extrapolation of doses from adults could be harmful for children as the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB) function is still immature. More specifically, age-related variation in membrane transporters may impact brain disposition. As human data on brain transporter expression is scarce, age dependent [gestational age (GA), postnatal age (PNA), and postmenstrual age (PMA)] variation in immunohistochemical localization and staining intensity of the ABC transporters P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), and multidrug resistance-associated proteins 1, 2, 4, and 5 (MRP1/2/4/5) was investigated. Post mortem brain cortical and ventricular tissue was derived from 23 fetuses (GA range 12.9-39 weeks), 17 neonates (GA range 24.6-41.3 weeks, PNA range 0.004-3.5 weeks), 8 children (PNA range 0.1-3 years), and 4 adults who died from a wide variety of underlying conditions. In brain cortical BBB, immunostaining increased with age for Pgp and BCRP, while in contrast, MRP1 and MRP2 staining intensity appeared higher in fetuses, neonates, and children, as compared to adults. BCSFB was positively stained for Pgp, MRP1, and MRP2 and appeared stable across age, while BCRP was not detected. MRP4 and MRP5 were not detected in BBB or BCSFB. In conclusion, human BBB and BCSFB ABC membrane transporters show brain location and transporter-specific maturation.

Intranasal delivery of quercetin-loaded mucoadhesive nanoemulsion for treatment of cerebral ischaemia.

BACKGROUND: Quercetin (QUR), as an antioxidant flavonoid, exhibits potential role in the amelioration of cerebral ischaemia; however, poor solubility as well as oral absorption results low serum and tissue levels for this drug. PURPOSE OF THE STUDY: To enhance bioavailability, this study aims to prepare QUR nanoemulsions and administer via non-invasive nasal route in order to evaluate the drug targeting in brain. METHODS: Quercetin mucoadhesive nanoemulsion (QMNE) was prepared (ionic gelation method) and optimized using various parameters, that is, particle size, entrapment efficiency, zeta potential and ex vivo permeation study. RESULTS: The results observed for optimized QMNE were as follows: mean globule size (91.63 ± 4.36 nm), zeta potential (-17.26 ± 1.04 mV), drug content (99.84 ± 0.34%) and viscosity (121 ± 13 cp). To evaluate the extent of bioavailability for QMNE via post-intranasal (i.n.) administration, Ultra performance liquid chromatography-mass spectroscopy (UPLC-ESI-Q-TOF-MS/MS)-based bioanalytical method was developed and validated for pharmacokinetics, biodistribution, brain-targeting efficiency (9333.33 ± 39.39%) and brain drug-targeting potential (2181.83 ± 5.69%) which revealed enhanced QUR brain bioavailability as compared to intravenous administration (i.v.). Furthermore, improved neurobehavioral activity (locomotor and grip strength), histopathology and reduced infarction volume effects were observed in middle cerebral artery occlusion (MCAO)-induced cerebral ischemic rats model after i.n. administration of QMNE. CONCLUSION: This study supports a significant role for QMNE in terms of high brain-targeting potential and formulation efficiency due to ease of access and effective targeting in brain.

Comparative brain pharmacokinetic study of Jiaotai pills in normal and insomnic rats using brain microdialysis combinated with LC–MS/MS / 中草药·英文版

Objective: To compare the brain pharmacokinetics of five protoberberine-type alkaloids (i.e. berberine, palmatine, coptisine, epiberberine, and jatrorrhizine), which were the main bioactive constituents of Jiaotai Pills (JTP), in normal and insomnic rats orally administrated with JTP. Methods: The detection was conducted by a fully validated liquid chromatography-tandem mass spectrometry combinated with brain microdialysis method. Brain microdialysis probes were inserted into the hippocampus of rats. JTP extracts were administrated intragastrically and then brain microdialysates were collected at 30 min time intervals for 10 h. The separation of the five protoberberine-type alkaloids was carried out on a BDS Hypersil C18 column using a mobile phase consisting of acetonitrile and water (containing 5 mmol ammonium acetate adjusted to pH 5.0) within 4 min. The quantification was performed by multiple reaction monitoring with the transitions of m/z 336.0-320.1 for berberine, m/z 352.0-336.1 for palmatine, m/z 338.0-322.1 for jatrorrhizine, m/z 336.0-320.1 for epiberberine, m/z 320.0-292.1 for coptisine and m/z 356.4-192.1 for IS. Results: The lower limit of quantification for five protoberberine-type alkaloids was 0.05 ng/mL. Linearity, accuracy, precision, stability and matrix effect of five analytes were all satisfactory. Five protoberberine-type alkaloids were quickly distributed in the brain. Moreover, significant differences in the principal pharmacokinetic parameters such as AUC and T1/2 of the analytes were observed between two groups. Conclusion: The LC-MS/MS method combinated with microdialysis is useful in the brain pharmacokinetic study of five protoberberine-type alkaloids. The results indicated that the rates of analytes absorption in insomnic rats were significantly higher than those in normal rats. Besides, the protoberberine-type alkaloids could bring a direct effect on the neuron in the hippocampus.

Effect of ferulic acid on the brain pharmacokinetics of tetramethylpyrazine in conscious rats.

1. In traditional Chinese medicine, Angelica sinensis is often coprescribed with Ligusticum chuanxiong Hort for the treatment of ischemic cerebrovascular diseases. Tetramethylpyrazine (TMP) is one of the most important active ingredients isolated from Ligusticum chuanxiong Hort; ferulic acid (FA) is the main water-soluble component of Angelica sinensis. 2. The purpose of this study is to investigate the possible effect of FA on the brain pharmacokinetics of TMP in conscious Sprague-Dawley rats. The pharmacokinetic parameters of TMP were investigated in brain microdialysates after oral and intravenous administration of TMP (4 mg/kg) to rats in the absence and presence of FA (5 mg/kg). Samples were collected at timed intervals for the measurement of TMP by a rapid and sensitive UPLC-MS/MS method. 3. The pharmacokinetic parameters were calculated by noncompartmental analysis for brain microdialysates. The brain pharmacokinetic data for TMP showed significant increases in Cmax, t1/2, AUC0-inf and MRT0-inf after combination with FA. After intragastric administration with FA, there were significant decreases in the Tmax (from 38.33 ± 5.77 to 21 ± 5.48 min; p < 0.01) of TMP. This study indicated that potential drug-drug interaction between TMP and FA should be taken into consideration and the combined administration is beneficial in improving the bioavailability of TMP in the brain.

Rutin-encapsulated chitosan nanoparticles targeted to the brain in the treatment of Cerebral Ischemia.

OBJECTIVE: Rutin, a potent antioxidant, has been reported to reduce the risk of ischemic disease. Our study aims to prepare rutin-encapsulated-chitosan nanoparticles (RUT-CS-NPs) via ionic gelation method and determine its results, based on different parameters i.e. surface morphology characterization, in-vitro or ex-vivo release, dynamic light scattering and differential scanning calorimetry (DSC), for treating cerebral ischemia. METHODS: UPLC-ESI-Q-TOF-MS/MS was used to evaluate the optimized RT-CS-NPs1 for brain-drug uptake as well as to follow-up the pharmacokinetics, bio-distrbution, brain-targeting efficiency and potential after intranasal administration (i.n.). KEY FINDINGS: A particle size of <100nm for the formulation, significantly affected by drug:CS ratio, and entrapment efficiency and loading capacity of 84.98%±4.18% and 39.48%±3.16%, respectively were observed for RUT. Pharmacokinetics, bio-distribution, brain-targeting efficiency (1443.48±39.39%) and brain drug-targeting potential (93.00±5.69%) showed enhanced bioavailability for RUT in brain as compared to intravenous administration. In addition; improved neurobehavioral activity, histopathology and reduced infarction volume effects were observed in middle cerebral artery occlusion (MCAO) induced cerebral ischemic rats model after i.n. administration of RUT-CS-NPs. CONCLUSION: A significant role of mucoadhesive-RT-CS-NPs1 as observed after high targeting potential and efficiency of the formulation prove; RUT-CS-NPs are more effectively accessed and target easily the brain.