Free interstitial levels of metformin in the liver of healthy and diabetic Wistar rats

Abstract In the present study, free interstitial levels reached by metformin in the liver were investigated in control and diabetic rats by microdialysis. Firstly, a bioanalytical method using an HPLC-UV system to determine the drug concentration in microdialysis samples was validated. The blood glucose levels and biochemical parameters were investigated in control and diabetic animals. Following that, both groups received a dose of 50 mg/kg of metformin iv bolus and the free interstitial levels reached in the liver were assessed by microdialysis. The method was validated according to FDA guidelines being suitable to quantify free concentrations of metformin in the liver of control and diabetics rats. Free exposure to metformin was similar in control and diabetic animals: AUC0-∞ 118.50 ± 40.18 vs 112.93 ± 50.25 µg.h/mL, respectively. The half-life in tissue was similar to that described in the literature for plasma. Hence diabetes induced by streptozotocin after administration of nicotinamide in our study did not damage the renal and hepatic function of the animals. The levels reached in the liver were 1.6 times higher than the free plasma concentrations, demonstrating higher liver penetration of metformin. This is the first investigation in liver interstitial concentration of metformin in control and diabetic rats

Microdialysis and microperfusion electrodes in neurologic disease monitoring.

Contemporary biomarker collection techniques in blood and cerebrospinal fluid have to date offered only modest clinical insights into neurologic diseases such as epilepsy and glioma. Conversely, the collection of human electroencephalography (EEG) data has long been the standard of care in these patients, enabling individualized insights for therapy and revealing fundamental principles of human neurophysiology. Increasing interest exists in simultaneously measuring neurochemical biomarkers and electrophysiological data to enhance our understanding of human disease mechanisms. This review compares microdialysis, microperfusion, and implanted EEG probe architectures and performance parameters. Invasive consequences of probe implantation are also investigated along with the functional impact of biofouling. Finally, previously developed microdialysis electrodes and microperfusion electrodes are reviewed in preclinical and clinical settings. Critically, current and precedent microdialysis and microperfusion probes lack the ability to collect neurochemical data that is spatially and temporally coincident with EEG data derived from depth electrodes. This ultimately limits diagnostic and therapeutic progress in epilepsy and glioma research. However, this gap also provides a unique opportunity to create a dual-sensing technology that will provide unprecedented insights into the pathogenic mechanisms of human neurologic disease.

Early detection of complications in pancreas transplants by microdialysis catheters, an observational feasibility study.

BACKGROUND: Despite advances in immunosuppression and surgical technique, pancreas transplantation is encumbered with a high rate of complication and graft losses. Particularly, venous graft thrombi occur relatively frequently and are rarely detected before the transplant is irreversibly damaged. METHODS: To detect complications early, when the grafts are potentially salvageable, we placed microdialysis catheters anteriorly and posteriorly to the graft in a cohort of 34 consecutive patients. Glucose, lactate, pyruvate, and glycerol were measured at the bedside every 1-2 hours. RESULTS: Nine patients with graft venous thrombosis had significant lactate and lactate-to-pyruvate-ratio increases without concomitant rise in blood glucose or clinical symptoms. The median lactate in these patients was significantly higher in both catheters compared to non-events (n = 15). Out of the nine thrombi, four grafts underwent successful angiographic extraction, one did not require intervention and four grafts were irreversibly damaged and explanted. Four patients with enteric anastomosis leakages had significantly higher glycerol measurements compared to non-events. As with the venous thrombi, lactate and lactate-to-pyruvate ratio were also increased in six patients with graft surrounding hematomas. CONCLUSIONS: Bedside monitoring with microdialysis catheters is a promising surveillance modality of pancreatic grafts, but differentiating between the various pathologies proves challenging.

Cerebral Microdialysis as a Tool for Assessing the Delivery of Chemotherapy in Brain Tumor Patients.

The development of curative treatment for glioblastoma has been extremely challenging. Chemotherapeutic agents that have seemed promising have failed in clinical trials. Drugs that can successfully target cancer cells within the brain must first traverse the brain interstitial fluid. Cerebral microdialysis (CMD) is an invasive technique in which interstitial fluid can be directly sampled. CMD has primarily been used clinically in the setting of head trauma and subarachnoid hemorrhage. Our goal was to review the techniques, principles, and new data pertaining to CMD to highlight its use in neuro-oncology. We conducted a literature search using the PubMed database and selected studies in which the investigators had used CMD in either animal brain tumor models or clinical trials. The references were reviewed for additional information. Studies of CMD have shown its importance as a neurosurgical technique. CMD allows for the collection of pharmacokinetic data on drug penetrance across the blood-brain barrier and metabolic data to characterize the response to chemotherapy. Although no complications have been reported, the current CMD technique (as with any procedure) has risks and limitations, which we have described in the present report. Animal CMD experiments have been used to exclude central nervous system drug candidates from progressing to clinical trials. At present, patients undergoing CMD have been monitored in the intensive care unit, owing to the requisite tethering to the apparatus. This can be expected to change soon because of advances in microminiaturization. CMD is an extremely valuable, yet underused, technique. Future CMD applications will have central importance in assessing drug delivery to tumor cells in vivo, allowing a pathway to successful therapy for malignant brain tumors.

Interaction between Mesocortical and Mesothalamic Catecholaminergic Transmissions Associated with NMDA Receptor in the Locus Coeruleus.

Noncompetitive N-methyl-D-aspartate/glutamate receptor (NMDAR) antagonists contribute to the pathophysiology of schizophrenia and mood disorders but improve monoaminergic antidepressant-resistant mood disorder and suicidal ideation. The mechanisms of the double-edged sword clinical action of NMDAR antagonists remained to be clarified. The present study determined the interaction between the NMDAR antagonist (MK801), α1 adrenoceptor antagonist (prazosin), and α2A adrenoceptor agonist (guanfacine) on mesocortical and mesothalamic catecholaminergic transmission, and thalamocortical glutamatergic transmission using multiprobe microdialysis. The inhibition of NMDAR in the locus coeruleus (LC) by local MK801 administration enhanced both the mesocortical noradrenergic and catecholaminergic coreleasing (norepinephrine and dopamine) transmissions. The mesothalamic noradrenergic transmission was also enhanced by local MK801 administration in the LC. These mesocortical and mesothalamic transmissions were activated by intra-LC disinhibition of transmission of γ-aminobutyric acid (GABA) via NMDAR inhibition. Contrastingly, activated mesothalamic noradrenergic transmission by MK801 enhanced intrathalamic GABAergic inhibition via the α1 adrenoceptor, resulting in the suppression of thalamocortical glutamatergic transmission. The thalamocortical glutamatergic terminal stimulated the presynaptically mesocortical catecholaminergic coreleasing terminal in the superficial cortical layers, but did not have contact with the mesocortical selective noradrenergic terminal (which projected terminals to deeper cortical layers). Furthermore, the α2A adrenoceptor suppressed the mesocortical and mesothalamic noradrenergic transmissions somatodendritically in the LC and presynaptically/somatodendritically in the reticular thalamic nucleus (RTN). These discrepancies between the noradrenergic and catecholaminergic transmissions in the mesocortical and mesothalamic pathways probably constitute the double-edged sword clinical action of noncompetitive NMDAR antagonists.

The Importance of Probe Location for the Interpretation of Cerebral Microdialysis Data in Subarachnoid Hemorrhage Patients.

BACKGROUND: There is no uniform definition for cerebral microdialysis (CMD) probe location with respect to focal brain lesions, and the impact of CMD-probe location on measured molecule concentrations is unclear. METHODS: We retrospectively analyzed data of 51 consecutive subarachnoid hemorrhage patients with CMD-monitoring between 2010 and 2016 included in a prospective observational cohort study. Microdialysis probe location was assessed on all brain computed tomography (CT) scans performed during CMD-monitoring and defined as perilesional in the presence of a focal hypodense or hyperdense lesion within a 1-cm radius of the gold tip of the CMD-probe, or otherwise as normal-appearing brain tissue. RESULTS: Probe location was detected in normal-appearing brain tissue on 53/143 (37%) and in perilesional location on 90/143 (63%) CT scans. In the perilesional area, CMD-glucose levels were lower (p = 0.003), whereas CMD-lactate (p = 0.002), CMD-lactate-to-pyruvate-ratio (LPR; p < 0.001), CMD-glutamate (p = 0.002), and CMD-glycerol levels (p < 0.001) were higher. Neuroglucopenia (CMD-glucose < 0.7 mmol/l, p = 0.002), metabolic distress (p = 0.002), and mitochondrial dysfunction (p = 0.005) were more common in perilesional compared to normal-appearing brain tissue. Development of new lesions in the proximity of the CMD-probe (n = 13) was associated with a decrease in CMD-glucose levels, evidence of neuroglucopenia, metabolic distress, as well as increasing CMD-glutamate and CMD-glycerol levels. Neuroglucopenia was associated with poor outcome independent of probe location, whereas elevated CMD-lactate, CMD-LPR, CMD-glutamate, and CMD-glycerol levels were only predictive of poor outcome in normal-appearing brain tissue. CONCLUSIONS: Focal brain lesions significantly impact on concentrations of brain metabolites assessed by CMD. With the exception of CMD-glucose, the prognostic value of CMD-derived parameters seems to be higher when assessed in normal-appearing brain tissue. CMD was sensitive to detect the development of new focal lesions in vicinity to the neuromonitoring probe. Probe location should be described in the research reporting brain metabolic changes measured by CMD and integrated in statistical models.

A rotating operant chamber for use with microdialysis.

BACKGROUND: Recently, the time resolution of microdialysis followed by a chemical separation for quantitative analysis has improved. The advent of faster microdialysis measurements promises to aid in behavioral research on awake animals. However, microdialysis with awake animals generally employs a fluidic commutator (swivel). The swivel's volume is inimical to the time resolution of the measurements. NEW METHOD: Animals can be housed in rotating cages so that the swivel is not required, but rotating operant chambers are not available. Here we describe the design and construction of a rotating operant chamber with microdialysis capability. We modified a rotating cage by adding operant behavior testing components to the side of the bowl-shaped cage. A modular on-board controller facilitates operant component/computer communication. A battery provides power to the controller and the operant components. The battery and controller rotate with the cage, and the controller communicates with the computer wirelessly. RESULTS: The rotating operant chamber can be used to train a rat to retrieve a sucrose pellet following a cue. Microdialysis and online liquid chromatography can be used to measure dopamine at one minute intervals while the rat moves freely and interacts with operant behavior testing components. COMPARISON WITH EXISTING METHOD(S): We are not aware of one-minute dopamine measurements in awake animals in an operant chamber. CONCLUSIONS: Rotating cage modifications are straightforward. One-minute observations of striatal dopamine can be accomplished while an animal is awake, moving, and interacting with its surroundings.

In vitro evaluation of an intravenous microdialysis catheter for therapeutic drug monitoring of gentamicin and vancomycin.

A central venous catheter with a built-in microdialysis membrane is available for continuous lactate and glucose monitoring in the intensive care unit (ICU). As this catheter might also be suitable for repeated measurements of unbound drug levels, we studied in vitro the feasibility of monitoring unbound antibiotic concentrations. The catheter was placed in various media at 37°C spiked with gentamicin or vancomycin. Dialysate fractions were repeatedly collected over 3 hours with a NaCl 0.9% perfusate flow of 5 µL/min. Total and unbound drug concentrations in medium and perfusate were measured by immunoassay. After 60 minutes stable recovery for both drugs was observed, with mean ±SD relative recoveries of vancomycin and gentamicin in human serum of 64% ±0.4% and 73% ±3%. The recoveries of the unbound concentrations were 91% ±3% and 91% ±4%. This intravenous microdialysis system may be a very useful platform for therapeutic drug monitoring in the ICU.

Consequence of insertion trauma - effect on early measurements when using intracerebral devices.

There are a variety of devices that quantify biological properties of cerebral tissue. Installing such device will cause a local insertion trauma, which will affect early measurements. Current literature proposes minimum one hour of observation before acquiring first measurements when using microdialysis. It is unknown whether this applies to other intracerebral devices. We therefore aimed to investigate time needed to reach steady state when using microdialysis and two intracerebral probes in a piglet model. Ten newborn piglets less than 24 hours of age were anaesthetized. Two probes (Codman and OxyLite/OxyFlo) and a microdialysis catheter (CMA Microdialysis) were installed 10 mm into the left hemisphere. Probes measured intracranial pressure, cerebral blood flow, and oxygen tension. The microdialysis catheter measured lactate, glucose, glycerol, and pyruvate. Measurements were acquired hourly for 20 hours. Lactate and glycerol peaked immediately after insertion and reached steady state after approximately four hours. Glucose, pyruvate, cerebral blood flow, and intracranial pressure reached steady state immediately. Oxygen tension reached steady state after 12 hours. With time, interindividual variability decreased for the majority of measurements. Consequently, time to stabilization after insertion depends on the choice of device and is crucial to obtain valid baseline values with high degree of precision.

In vivo monitoring of cerebral glucose with an updated on-line electroanalytical system.

Because cerebral species involve rapid events, increasing the temporal resolution to realize in vivo near-real-time measurements is desirable. Here, we aimed to improve the low resolution of our previous on-line electroanalytical system by decreasing the dead volume and reducing molecular dispersion. This updated system has advantages of elevated time resolution and accelerated analysis for on-line monitoring of glucose versus the previous system. Finally, this new system was successfully applied to continuous measurement of cerebral glucose in vivo during global ischemia/reperfusion events. This study is expected to offer a reliable on-line analytical platform for continuous monitoring of important species associated with fast physiological and pathological events in vivo. Graphical abstract.

Monitoring biomolecule concentrations in tissue using a wearable droplet microfluidic-based sensor.

Knowing how biomarker levels vary within biological fluids over time can produce valuable insight into tissue physiology and pathology, and could inform personalised clinical treatment. We describe here a wearable sensor for monitoring biomolecule levels that combines continuous fluid sampling with in situ analysis using wet-chemical assays (with the specific assay interchangeable depending on the target biomolecule). The microfluidic device employs a droplet flow regime to maximise the temporal response of the device, using a screw-driven push-pull peristaltic micropump to robustly produce nanolitre-sized droplets. The fully integrated sensor is contained within a small (palm-sized) footprint, is fully autonomous, and features high measurement frequency (a measurement every few seconds) meaning deviations from steady-state levels are quickly detected. We demonstrate how the sensor can track perturbed glucose and lactate levels in dermal tissue with results in close agreement with standard off-line analysis and consistent with changes in peripheral blood levels.

3D printed microfluidic device for online detection of neurochemical changes with high temporal resolution in human brain microdialysate.

This paper presents the design, optimisation and fabrication of a mechanically robust 3D printed microfluidic device for the high time resolution online analysis of biomarkers in a microdialysate stream at microlitre per minute flow rates. The device consists of a microfluidic channel with secure low volume connections that easily integrates electrochemical biosensors for biomarkers such as glutamate, glucose and lactate. The optimisation process of the microfluidic channel fabrication, including for different types of 3D printer, is explained and the resulting improvement in sensor response time is quantified. The time resolution of the device is characterised by recording short lactate concentration pulses. The device is employed to record simultaneous glutamate, glucose and lactate concentration changes simulating the physiological response to spreading depolarisation events in cerebrospinal fluid dialysate. As a proof-of-concept study, the device is then used in the intensive care unit for online monitoring of a brain injury patient, demonstrating its capabilities for clinical monitoring.

Proteomic analysis and ATP assay reveal a positive effect of artificial cerebral spinal fluid perfusion following microdialysis sampling on repair of probe-induced brain damage.

BACKGROUND: Microdialysis (MD) is conventionally used to measure the in vivo levels of various substances and metabolites in extracellular and cerebrospinal fluid of brain. However, insertion of the MD probe and subsequent perfusion to obtain samples cause damage in the vicinity of the insertion site, raising questions regarding the validity of the measurements. NEW METHOD: We used fluorogenic derivatization liquid chromatography-tandem mass spectrometry, that quantifies both high and low abundance proteins, to differentiate the effects of perfusion from the effects of probe insertion on the proteomic profiles of expressed proteins in rat brain. RESULTS: We found that the expression levels of five proteins were significantly lower in the perfusion group than in the non-perfusion group. Three of these proteins are directly involved in ATP synthesis. In contrast to decreased levels of the three proteins involved in ATP synthesis, ATP assays show that perfusion, following probe insertion, even for a short time (3 h) increased ATP level up to 148% that prior to perfusion, and returned it to normal state (before probe insertion). COMPARISON WITH EXISTING METHOD: There is essentially no information regarding which observed changes are due to probe insertion and which to perfusion. CONCLUSIONS: Our findings partially demonstrate that the influence of whole MD sampling process may not significantly compromise brain function and subsequent analytical results may have physiological equivalence to normal, although energy production is transiently damaged by probe insertion.

Development of a highly sensitive gas chromatography-mass spectrometry method preceded by solid-phase microextraction for the analysis of propofol in low-volume cerebral microdialysate samples.

To date, the commonly used intravenous anesthetic propofol has been widely studied, and fundamental pharmacodynamic and pharmacokinetic characteristics of the drug are known. However, propofol has not yet been quantified in vivo in the target organ, the human brain. Here, cerebral microdialysis offers the unique opportunity to sample propofol in the living human organism. Therefore, a highly sensitive analytical method for propofol quantitation in small sample volumes of 30 µL, based on direct immersion solid-phase microextraction was developed. Preconcentration was followed by gas chromatographic separation and mass spectrometric detection of the compound. This optimized method provided a linear range between the lower limit of detection (50 ng/L) and 200 µg/L. Matrix-matched calibration was used to compensate recovery issues. A precision of 2.7% relative standard deviation between five consecutive measurements and an interday precision of 6.4% relative standard deviation could be achieved. Furthermore, the permeability of propofol through a cerebral microdialysate system was tested. In summary, the developed method to analyze cerebral microdialysate samples, allows the in vivo quantitation of propofol in the living human brain. Additionally the calculation of extracellular fluid levels is enabled since the recovery of the cerebral microdialysis regarding propofol was determined.

Sensitive targeted methods for brain metabolomic studies in microdialysis samples.

In vivo determination of brain mediators plays an important role in providing insight in how the brain functions. For this purpose, targeted metabolomics can be a very useful tool. Targeted metabolomics detects and measures certain known low-molecular-weight biomolecules involved in signaling pathways and biochemical processes in the central nervous system. Microdialysis is a powerful technique to sample brain mediators in the central nervous system. Several analytical techniques that can possibly be coupled to microdialysis are available. However, selection of an appropriate technique should be considered carefully, since sensitivity and specificity are critical when measuring these mediators in volume-restricted microdialysis samples. This review outlines some of the commonly applied sampling methods and analytical techniques and discusses some of the challenges encountered during the in vivo determination of central nervous system mediators.

Neurochemistry of Anesthetic States.

Anesthetic mechanisms that eliminate consciousness and perception of pain are products of the nervous system. Chemical approaches to the study of anesthetic mechanisms have the potential to serve as an ideal interface between basic and clinical neuroscience. There are disproportionately more basic neurochemical studies than clinical studies of anesthetic mechanisms. Even within neuroscience, the study of anesthetic mechanisms is sparse. The Society for Neuroscience hosts one of the world's largest and most vibrant scientific meetings, yet the content themes of that meeting do not include anesthesia. One goal of this chapter is to facilitate neurochemical studies of anesthetic mechanisms by outlining user-friendly descriptions of existing and emerging techniques. The introduction provides a context for chapter goals. The second portion of this chapter focuses on microdialysis methods that enable the humane acquisition of neurochemical samples from intact, behaving animals during anesthetic induction, maintenance, and emergence. No single neurotransmitter and no single brain region regulate the physiological and behavioral traits characteristic of any anesthetic state. This limitation is being addressed via application of new instrumentation and techniques in analytic chemistry. The final third of this chapter highlights selected omics approaches that are now being applied to the neurochemical study of anesthetic mechanisms. We hope that this brief chapter can stimulate basic and clinical metabolomic approaches aiming to elucidate the mechanisms of anesthetic action.

A simple blood microdialysis in freely-moving rats for pharmacokinetic-pharmacodynamic modeling study of Shengmai injection with simultaneous determination of drug concentrations and efficacy levels in dialysate.

Microdialysis is a powerful in vivo sampling technique for pharmacokinetic-pharmacodynamic (PK-PD) modeling of drugs in pre-clinical and clinical studies. However, the noticeable limitations of previous studies using microdialysis were that animals anesthesia in the whole experiment and the combination of microdialysis and blood sampling for drug and (or) effect detection, which can obviously influence PK and PD behavior of drugs. In this study, a simple blood microdialysis sampling system in freely-moving rats was established for simultaneous study of PK and PD of Shengmai injection (SMI) effect on inducing real-time nitric oxide (NO) release on isoproterenol (ISO) induced myocardial ischemia rats. The LC-MS/MS and HPLC with fluorescence detection (HPLC-FLD) methods were developed to determine ginsenside Rg1, Rg2, Re, Rf, Rb1, Rd and Rc, the main effective components of SMI, and NOx-, the main oxidation products of NO, in dialysates respectively. Through simultaneous determination of drug concentrations and NO efficacy levels in dialysate, the developed methods were successfully applied to set up concentration-time and effect-time profiles followed by PK-PD modeling of SMI effect on inducing NO release after intravenous administration of 10.8 mL kg-1 SMI in myocardial ischemia rats. The PK-PD modeling characterized the dose-effect relationships of SMI and behaved good prediction ability. The established blood microdialysis in freely-moving rats is an appealing technology for rational PK-PD studies when selecting suitable blood endogenous micromolecule as effect marker.

Assessment of changes in blood glucose concentration with intravascular microdialysis.

Blood glucose and its variability of is a major prognostic factor associated with morbidity. We hypothesized that intravenous microdialysis incorporated in a central venous catheter (CVC) would be interchangeable with changes in blood glucose measured by the reference method using a blood gas analyzer. Microdialysis and central venous blood glucose measurements were simultaneously recorded in high-risk cardiac surgical patients. The correlation between absolute values was determined by linear regression and the Bland-Altman test for repeated measurements was used to compare bias, precision, and limits of agreement. Changes in blood glucose measurement were evaluated by four-quadrant plot and trend interchangeability methods (TIM). In the 23 patients analyzed, the CVC was used as part of standard care with no complications. The correlation coefficient for absolute values (N = 99) was R = 0.91 (P < 0.001). The bias, precision and limits of agreement were - 9.1, 17.4 and - 43.2 to 24.9 mg/dL, respectively. The concordance rate for changes in blood glucose measurements (N = 77) was 85% with the four-quadrant plot. The TIM showed that 14 (18%) changes of blood glucose measurements were uninterpretable. Among the remaining 63 (82%) interpretable changes, 23 (37%) were interchangeable, 13 (20%) were in the gray zone, and 27 (43%) were not interchangeable. Microdialysis using a CVC appears to provide imprecise absolute blood glucose values with risk of insulin misuse. Moreover, only one third of changes in blood glucose measurements were interchangeable with the reference method using the TIM.

PDMS/glass hybrid device with a reusable carbon electrode for on-line monitoring of catecholamines using microdialysis sampling coupled to microchip electrophoresis with electrochemical detection.

On-line separations-based sensors employing microdialysis (MD) coupled to microchip electrophoresis (ME) enable the continuous monitoring of multiple analytes simultaneously. Electrochemical detection (EC) is especially amenable to on-animal systems employing MD-ME due to its ease of miniaturization. However, one of the difficulties in fabricating MD-ME-EC systems is incorporating carbon working electrodes into the device. In this paper, a novel fabrication procedure is described for the production of a PDMS/glass hybrid device that is capable of integrating hydrodynamic MD flow with ME-EC using a flow-gated interface and a pyrolyzed photoresist film carbon electrode. This fabrication method enables the reuse of carbon electrodes on a glass substrate, while still maintaining a good seal between the PDMS and glass to allow for pressure-driven MD flow. The on-line MD-ME-EC device was characterized in vitro and in vivo for monitoring analytes in the dopamine metabolic pathway. The ultimate goal is to use this device and associated instrumentation to perform on-animal, near-real time in vivo monitoring of catecholamines.

Pharmacokinetics of doxorubicin in glioblastoma multiforme following ultrasound-Induced blood-brain barrier disruption as determined by microdialysis.

The goal of this study was to investigate the in vivo extracellular kinetics of doxorubicin (Dox) in glioblastoma multiforme (GBM)-bearing mice following focused ultrasound (FUS)-induced blood-brain barrier (BBB) disruption using microdialysis. An intracranial brain tumor model in NOD-scid mice using human brain GBM 8401 cells was used in this study. Prior to each sonication, simultaneous intravenous administration of Dox and microbubbles, and the Dox concentration in the brains was quantified by high performance liquid chromatography (HPLC). Drug administration with sonication elevated the tumor-to-normal brain Dox ratio of the target tumors by about 2.35-fold compared with the control tumors. The mean peak concentration of Dox in the sonicated GBM dialysate was 10 times greater than without sonication, and the area under the concentration-time curve was 3.3 times greater. This study demonstrates that intracerebral microdialysis is an effective means of evaluating real-time target BBB transport profiles and offers the possibility of investigating the pharmacokinetics of drug delivery in the sonicated brain.