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The AAPS Journal Apr 2006Quantification of target site pharmacokinetics (PK) is crucial for drug discovery and development. Clinical microdialysis (MD) has increasingly been employed for the... (Comparative Study)
Comparative Study Review
Quantification of target site pharmacokinetics (PK) is crucial for drug discovery and development. Clinical microdialysis (MD) has increasingly been employed for the description of drug distribution and receptor phase PK of the unbound fraction of various analytes. Costs for MD experiments are comparably low and given suitable analytics, target tissue PK of virtually any drug molecule can be quantified. The major limitation of MD stems from the fact that organs such as brain, lung or liver are not readily accessible without surgery. Recently, non-invasive imaging techniques, i.e. positron emission tomography (PET) or magnetic resonance spectroscopy (MRS), have become available for in vivo drug distribution assessment and allow for drug concentration measurements in practically every human organ. Spatial resolution of MRS imaging, however, is low and although PET enables monitoring of regional drug concentration differences with a spatial resolution of a few millimetres, discrimination between bound and unbound drug or parent compound and metabolite is difficult. Radiotracer development is furthermore time and labour intensive and requires special expertise and radiation exposure and costs originating from running a PET facility cannot be neglected. The recent complementary use of MD and imaging has permitted to exploit individual strengths of these diverse techniques. In conclusion, MD and imaging techniques have provided drug distribution data that have so far not been available. Used alone or in combination, these methods may potentially play an important role in future drug research and development with the potential to serve as translational tools for clinical decision making.
Topics: Biopsy; Humans; Magnetic Resonance Spectroscopy; Microdialysis; Pharmacokinetics; Positron-Emission Tomography; Saliva; Skin; Tissue Distribution
PubMed: 16796376
DOI: 10.1007/BF02854896 -
Journal of Pharmaceutical and... Feb 2024Doxorubicin is a chemotherapeutic agent used for more than fifty years to treat a great variety of cancers in both children and adults. Despite hereof, pharmacokinetic...
Doxorubicin is a chemotherapeutic agent used for more than fifty years to treat a great variety of cancers in both children and adults. Despite hereof, pharmacokinetic knowledge is almost solely based on systemic plasma concentrations. Microdialysis is a catheter-based pharmacokinetic sampling tool enabling simultaneous target site sampling of unbound molecules of interest. The aim of this study was to thoroughly evaluate the feasibility of applying microdialysis for sampling of Doxorubicin in both in vitro experiments and an in vivo setting. Doxorubicin relative recovery by gain and by loss was tested for different catheter types, perfusion fluids, concentrations and collection vials. Adsorption tests revealed polystyrene/santoprene vials to be the biggest contributor of unwanted adsorption between Doxorubicin and the microdialysis equipment, and confirmed LoBind Eppendorf tubes to be a suitable alternative. The methodological combination of polyamide membranes, saline as perfusion fluid and LoBind Eppendorf sampling tubes demonstrated no statistically significant differences for relative recovery by gain and by loss, and the relative recovery was also found to be concentration independent. We conclude, that a proper microdialysis set-up can be used to collect samples containing concentrations of the chemotherapeutic drug Doxorubicin in vitro and in vivo, which encourage future pharmacokinetic studies to evaluate current treatment regimens to find the most effective and least toxic anti-neoplastic treatment for the patients.
Topics: Adult; Child; Humans; Microdialysis; Doxorubicin
PubMed: 38039870
DOI: 10.1016/j.jpba.2023.115872 -
Journal of Visualized Experiments : JoVE Jul 2015Microdialysis is a commonly used technique in neuroscience research. Therefore commercial probes are in great demand to monitor physiological, pharmacological and...
Microdialysis is a commonly used technique in neuroscience research. Therefore commercial probes are in great demand to monitor physiological, pharmacological and pathological changes in cerebrospinal fluid. Unfortunately, commercial probes are expensive for research groups in public institutions. In this work, a probe assembly is explained in detail to build a reliable, concentric, custom-made microdialysis probe for less than $10. The microdialysis probe consists of a polysulfone membrane with a molecular cut-off of 30 kDa. Probe in vitro recoveries of substances with different molecular weight (in the range of 100-1,600 Da) and different physicochemical properties are compared. The probe yields an in vitro recovery of approximately 20% for the small compounds glucose, lactate, acetylcholine and ATP. In vitro recoveries for neuropeptides with a molecular weight between 1,000-1,600 Da amount to 2-6%. Thus, while the higher molecular weight of the neuropeptides lowered in vitro recovery values, dialysis of compounds in the lower range (up to 500 Da) of molecular weights has no great impact on the in vitro recovery rate. The present method allows utilization of a dialysis membrane with other cut-off value and membrane material. Therefore, this custom-made probe assembly has the advantage of sufficient flexibility to dialyze substances in a broad molecular weight range. Here, we introduce a microdialysis probe with an exchange length of 2 mm, which is applicable for microdialysis in mouse and rat brain regions. However, dimensions of the probe can easily be adapted for larger exchange lengths to be used in larger animals.
Topics: Animals; Brain Chemistry; Equipment Design; Glucose; Lactic Acid; Mice; Microdialysis; Molecular Weight; Monitoring, Physiologic; Neuropeptides; Polymers; Rats; Sulfones
PubMed: 26273844
DOI: 10.3791/53048 -
Antimicrobial Agents and Chemotherapy Oct 2018The purpose of this study was to investigate aztreonam (ATM) and avibactam (AVI) distribution in intraperitoneal fluid and muscle interstitial fluid by microdialysis in...
The purpose of this study was to investigate aztreonam (ATM) and avibactam (AVI) distribution in intraperitoneal fluid and muscle interstitial fluid by microdialysis in rats, with or without peritonitis, and to compare the unbound concentrations in tissue with the unbound concentrations in blood. Microdialysis probes were inserted into the jugular veins, hind leg muscles, and peritoneal cavities of control rats ( = 5) and rats with intra-abdominal sepsis ( = 9) induced by cecal ligation and punctures. ATM and AVI probe recoveries in each medium were determined for both molecules in each rat by retrodialysis by drug. ATM-AVI combination was administered as an intravenous bolus at a dose of 100-25 mg · kg Microdialysis samples were collected over 120 min, and ATM-AVI concentrations were determined by liquid chromatography-tandem mass spectrometry. Noncompartmental pharmacokinetic analysis was conducted and nonparametric tests were used for statistical comparisons between groups (infected versus control) and medium. ATM and AVI distribution in intraperitoneal fluid and muscle was rapid and complete both in control rats and in rats with peritonitis, and the concentration profiles in blood, intraperitoneal fluid, and muscle were virtually superimposed, in control and infected animals, both for ATM and AVI. No statistically significant difference was observed between unbound tissue extracellular fluid and systemic areas under the curve for both molecules in control and infected animals. In the present study, intraperitoneal infection induced by cecal ligation and puncture had no apparent effect on ATM and AVI pharmacokinetics in rats.
Topics: Animals; Ascitic Fluid; Azabicyclo Compounds; Aztreonam; Male; Microdialysis; Muscle, Skeletal; Peritonitis; Rats; Rats, Sprague-Dawley
PubMed: 30012776
DOI: 10.1128/AAC.01228-18 -
The AAPS Journal Apr 2006In many cases the clinical outcome of therapy needs to be determined by the drug concentration in the tissue compartment in which the pharmacological effect occurs... (Review)
Review
In many cases the clinical outcome of therapy needs to be determined by the drug concentration in the tissue compartment in which the pharmacological effect occurs rather than in the plasma. Microdialysis is an in vivo technique that allows direct measurement of unbound tissue concentrations and permits monitoring of the biochemical and physiological effects of drugs throughout the body. Microdialysis was first used in pharmacodynamic research to study neurotransmission, and this remains its most common application in the field. In this review, we give an overview of the principles, techniques, and applications of microdialysis in pharmacodynamic studies of local physiological events, including measurement of endogenous substances such as acetylcholine, catecholamines, serotonin, amino acids, peptides, glucose, lactate, glycerol, and hormones. Microdialysis coupled with systemic drug administration also permits the more intensive examination of the pharmacotherapeutic effect of drugs on extracellular levels of endogenous substances in peripheral compartments and blood. Selected examples of the physiological effects and mechanisms of action of drugs are also discussed, as are the advantages and limitations of this method. It is concluded that microdialysis is a reliable technique for the measurement of local events, which makes it an attractive tool for local pharmacodynamic research.
Topics: Acetylcholine; Animals; Brain Chemistry; Catecholamines; Humans; Microdialysis; Neurotransmitter Agents; Pharmacology
PubMed: 16796373
DOI: 10.1007/BF02854892 -
The AAPS Journal Oct 2005In vivo microdialysis technique has become one of the major tools to sample endogenous and exogenous substances in extracellular spaces. As a well-validated sampling... (Review)
Review
In vivo microdialysis technique has become one of the major tools to sample endogenous and exogenous substances in extracellular spaces. As a well-validated sampling technique, microdialysis has been frequently employed for quantifying drug disposition at the desired target in both preclinical and clinical settings. This review addresses general methodological considerations critical to performing microdialysis in tumors, highlights selected preclinical and clinical studies that characterized drug disposition in tumors by the use of microdialysis, and illustrates the potential application of microdialysis in the assessment of tumor response to cancer treatment.
Topics: Animals; Antineoplastic Agents; Humans; Microdialysis; Neoplasms; Pharmacokinetics
PubMed: 16353942
DOI: 10.1208/aapsj070366 -
Journal of Visualized Experiments : JoVE Oct 2008The ability to measure extracellular basal levels of neurotransmitters in the brain of awake animals allows for the determination of effects of different systemic...
The ability to measure extracellular basal levels of neurotransmitters in the brain of awake animals allows for the determination of effects of different systemic challenges (pharmacological or physiological) to the CNS. For example, one can directly measure how the animal's midbrain dopamine projections respond to dopamine-releasing drugs like d-amphetamine or natural stimuli like food. In this video, we show you how to implant guide cannulas targeting specific sites in the rat brain, how to insert and implant a microdialysis probe and how to use high performance liquid chromatography coupled with electrochemical detection (HPLC-EC) to measure extracellular levels of oxidizable neurotransmitters and metabolites. Local precise introduction of drugs through the microdialysis probe allows for refined work on site specificity in a compound s mechanism of action. This technique has excellent anatomical and chemical resolution but only modest time resolution as microdialysis samples are usually processed every 20-30 minutes to ensure detectable neurotransmitter levels. Complementary ex vivo tools (i.e., slice and cell culture electrophysiology) can assist with monitoring real-time neurotransmission.
Topics: Animals; Brain; Brain Chemistry; Mice; Microdialysis; Neurotransmitter Agents; Rats; Stereotaxic Techniques
PubMed: 19078946
DOI: 10.3791/880 -
MAbs 2021The determination of concentrations of large therapeutic molecules, like monoclonal antibodies (mAbs), in the interstitial brain fluid (ISF) is one of the cornerstones... (Comparative Study)
Comparative Study
The determination of concentrations of large therapeutic molecules, like monoclonal antibodies (mAbs), in the interstitial brain fluid (ISF) is one of the cornerstones for the translation from preclinical species to humans of treatments for neurodegenerative diseases. Microdialysis (MD) and cerebral open flow microperfusion (cOFM) are the only currently available methods for extracting ISF, and their use and characterization for the collection of large molecules in rodents have barely started. For the first time, we compared both methods at a technical and performance level for measuring ISF concentrations of a non-target-binding mAb, trastuzumab, in awake and freely moving mice. Without correction of the data for recovery, concentrations of samples are over 10-fold higher through cOFM compared to MD. The overall similar pharmacokinetic profile and ISF exposure between MD (corrected for recovery) and cOFM indicate an underestimation of the absolute concentrations calculated with recovery. recovery (zero-flow rate method) revealed an increased extraction of trastuzumab at low flow rates and a 6-fold higher absolute concentration at steady state than initially calculated with the recovery. Technical optimizations have significantly increased the performance of both systems, resulting in the possibility of sampling up to 12 mice simultaneously. Moreover, strict aseptic conditions have played an important role in improving data quality. The standardization of these complex methods makes the unraveling of ISF concentrations attainable for various diseases and modalities, starting in this study with mAbs, but extending further in the future to RNA therapeutics, antibody-drug conjugates, and even cell therapies.
Topics: Animals; Antibodies, Monoclonal; Biomarkers; Brain; Extracellular Fluid; Mice; Microdialysis; Perfusion; Trastuzumab
PubMed: 33993834
DOI: 10.1080/19420862.2021.1918819 -
British Journal of Anaesthesia Aug 2012Cerebral microdialysis (MD) has proven to be a valuable clinical and research tool in neuroscience. It allows sampling of endogenous and exogenous molecules of interest... (Review)
Review
Cerebral microdialysis (MD) has proven to be a valuable clinical and research tool in neuroscience. It allows sampling of endogenous and exogenous molecules of interest from the extracellular fluid (ECF) of the brain. MD has also been successfully used to assess drug delivery to the target tissues in pharmacokinetic (PK) studies. There is a concern that due to the blood-brain barrier (BBB), current regimens of commonly used antibiotics might be inadequate. Although PK/pharmacodynamic (PK/PD) studies play an important role in drug evaluation, PK MD studies of antibacterial agents in cerebral tissue are few in number. These studies demonstrate a significant variation in drug penetration in the presence of intracranial pathology. Antibacterial agents from the same chemical group have significantly different PK profiles due to different affinity to the transport proteins of the BBB. Some studies suggest that commonly used antibiotics do not reach a therapeutic concentration range in brain ECF. Studies reviewed in this article are small and performed in different patient populations (brain tumour, head injury, epilepsy) using different methodological approaches to the drug recovery estimation. Nevertheless, they provide interesting and important data on the variability of antibiotic penetration that could be utilized for PK/PD studies and which may have clinical relevance.
Topics: Animals; Anti-Bacterial Agents; Blood-Brain Barrier; Brain; Humans; Microdialysis
PubMed: 22745353
DOI: 10.1093/bja/aes216 -
Diabetes Technology & Therapeutics Nov 2015Quantitative assessment of the dynamic relationship between plasma and interstitial fluid (ISF) glucose and the estimation of the plasma-to-ISF delay are of major...
BACKGROUND
Quantitative assessment of the dynamic relationship between plasma and interstitial fluid (ISF) glucose and the estimation of the plasma-to-ISF delay are of major importance to determine the accuracy of subcutaneous glucose sensors, an essential component of open- and closed-loop therapeutic systems for type 1 diabetes mellitus (T1DM). The goal of this work is to develop a model of plasma-to-ISF glucose kinetics from multitracer plasma and interstitium data, obtained by microdialysis, in healthy and T1DM subjects, under fasting conditions.
MATERIALS AND METHODS
A specific experimental design, combining administration of multiple tracers with the microdialysis technique, was used to simultaneously frequently collect plasma and ISF data. Linear time-invariant compartmental modeling was used to describe glucose kinetics from the tracer data because the system is in steady state.
RESULTS
A two-compartment model was shown accurate and was identified from both plasma and ISF data. An "equilibration time" between plasma and ISF of 9.1 and 11.0 min (median) in healthy and T1DM subjects, respectively, was calculated.
CONCLUSIONS
We have demonstrated that, in steady-state condition, the glucose plasma-to-ISF kinetics can be modeled with a linear two-compartment model and that the "equilibration time" between the two compartments can be estimated with precision. Future studies will assess plasma-to-interstitium glucose kinetics during glucose and insulin perturbations in both healthy and T1DM subjects.
Topics: Adult; Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 1; Extracellular Fluid; Fasting; Female; Healthy Volunteers; Humans; Kinetics; Linear Models; Male; Microdialysis; Middle Aged
PubMed: 26313215
DOI: 10.1089/dia.2015.0119