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PubMed2003

Assaying protein unbound drugs using microdialysis techniques.

Compared with traditional sampling methods, microdialysis is a technique for protein unbound drug sampling without withdrawal of biological fluids and involving minimal disturbance of physiological function. Conventional total drug sample consists of unbound drugs and protein bound drugs, which are loosely bound to plasma proteins such as albumin and alpha-1 acid glycoprotein, forming an equilibrium ratio between bound and unbound drugs. However, only the unbound fraction of drug is available for absorption, distribution, metabolism and elimination, and delivery to the target sites for pharmacodynamic actions. Although several techniques have been used to determine protein unbound drugs from biological fluids, including ultrafiltration, equilibrium dialysis and microdialysis, only microdialysis allows simultaneous sampling of protein unbound chemicals from plasma, tissues and body fluids such as the bile juice and cerebral spinal fluid for pharmacokinetic and pharmacodynamic studies. This review article describes the technique of microdialysis and its application in pharmacokinetic studies. Furthermore, the advantages and limitations of microdialysis are discussed, including the detailed surgical techniques in animal experiments from rat blood, brain, liver, bile duct and in vitro cell culture for unbound drug analysis.

Microdialysis↗
PubMed2005

Microdialysis of proteins: performance of the CMA/20 probe.

Unlike all other currently available sampling techniques, microdialysis allows the continuous recovery of dialysed fluid from the interstitial space of living tissue. Microdialysis has been extensively used to study small molecules such as neurotransmitters, metabolites and drugs in the brain and other tissues. There has been increasing interest in measuring proteins using microdialysis. Optimizing protein recovery requires slow buffer flow rates, large pore membranes and osmotic balancing. An examination of a widely used commercially available large pore (100kDa MWCO) polymeric microdialysis probe, the CMA/20 (polyethersulfone) over 6 days of continuous microdialysis showed that: (1) published molecular weight cut-off values may not predict the size of proteins that can be recovered. This membrane had an effective molecular weight cut-off values (MWCO) of about 29kDa, (2) protein recoveries decrease over time, (3) small proteins are much less affected than larger ones and (4) there can be significant differences in the recovery of proteins similar in size perhaps due to reaching of a critical size, protein aggregation, shape, surface charge or hydrophobicity.

Catheterization↗
PubMed2004

In vitro microdialysis sampling of docetaxel.

Microdialysis is a technique that allows sampling compounds from the extracellular fluid in different tissues, such as muscle, lung, and brain. However, the feasibility of using this technique with lipopohilic and high molecular weight compounds has been questioned, since these compounds are less likely to diffuse through the dialysis membrane. Therefore, it was the objective of this study to investigate the feasibility of doing microdialysis of docetaxel by determining its recovery by the microdialysis probe. Three different methods were investigated: extraction efficiency, retrodialysis, and no-net-flux. For the first two methods, three different concentrations were tested: 2.5, 5, and 9 mg/l. The recovery obtained for each concentration was 49.3 +/- 6.7 (n = 4), 44.6 +/- 5.4 (n = 3), and 34.7 +/- 2.1 (n = 4) by extraction efficiency, and 53.4 +/- 7.9 (n = 3), 61.4 +/- 7.6 (n = 3), and 64.2 +/- 1.9 (n = 3) by retrodialysis, respectively. The average recovery obtained by no-net-flux was 68.7 +/- 9.6 (n = 5). Although it has been reported that microdialysis cannot be applied to lipophilic compounds, the results here show the opposite. The high recoveries obtained for docetaxel in all methods applied show that the compound can diffuse through the probe membrane. Overall, docetaxel seems to be very suitable for microdialysis despite its lipophilicity and high molecular weight.

Docetaxel↗
PubMed2005

Multiplexed cytokine detection in microliter microdialysis samples obtained from activated cultured macrophages.

Microdialysis sampling probes were used to collect cytokine samples from lipopolysaccharide (LPS)-stimulated macrophages. The probes were immersed into cell culture wells containing either RAW 264.7 or isolated peritoneal macrophages. Dialysates (15 microL) from these wells were subjected to a multiplexed cytokine sandwich immunoassay platform analyzed by flow cytometry that measures up to six separate cytokines, interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-12p70 (IL-12p70), interferon-gamma (IFN-gamma), macrophage chemoattractant protein-1 (MCP-1), and tumor necrosis factor-alpha (TNF-alpha) in a single 15-muL sample. In vitro microdialysis sampling relative recovery experiments showed that only IFN-gamma, IL-6, MCP-1, and TNF-alpha could be recovered across a commercially-available 100-kDa MWCO microdialysis membrane. Eleven hours after LPS addition (1 microg/mL), RAW 264.7 macrophages secreted greater than 8000 pg/mL of TNF-alpha and greater than 1000 pg/mL MCP-1. With the peritoneal macrophages, greater than 6000 pg/mL of IL-6, MCP-1, and TNF-alpha were obtained. The maximum dialysate concentrations obtained from the RAW macrophages were 1300 pg/mL for TNF-alpha and 55 pg/mL for MCP-1. Maximum cytokine concentrations from peritoneal macrophage dialysates reached approximately 2000 pg/mL, 1100 pg/mL and 500 pg/mL for TNF-alpha, MCP-1 and IL-6, respectively. Microdialysis sampling allowed for 20-min samples to be collected during the cytokine release from the activated macrophages. These results demonstrate that microdialysis sampling can be used for collection of selected cytokines with improved temporal resolution.

Animals↗
PubMed2005

Urea as an endogenous surrogate in human microdialysis to determine relative recovery of drugs: analytics and applications.

During in vivo microdialysis studies time-consuming and laborious bedside calibration methods, e.g. retrodialysis, have to be performed. To reduce the burden on the patient it would be desirable to establish a reliable, time-saving calibration technique to obtain the in vivo recovery describing the relative drug transfer across the membrane of the microdialysis probe. The performed study aimed to evaluate and validate the use of urea as an endogenous reference compound to determine relative in vivo recovery of anti-infectives, e.g. linezolid used herein as model drug. In order to meet the special requirements imposed by microdialysis to measure urea concentrations in very small sample volumes ( approximately 10 microL) a photometric assay in 96-well microtiter plates was established based on the method of Berthelot. Subsequently, concentration- and flow rate-dependence were evaluated in vitro to determine the relative recovery (RR) of urea. Finally, urea and linezolid concentrations in human microdialysis samples were measured. The developed assay was validated according to international guidelines and met all requirements. Relative in vitro recovery was found to be independent from concentration and dependent on flow rate. Subsequently, relative in vivo recovery of urea was correlated with relative in vivo recovery of linezolid obtained by the traditional retrodialysis method. In healthy volunteers, the mean ratio of the relative recovery of linezolid to the relative recovery of urea was 0.6 for the subcutaneous (s.c.: CV 33.4%, n = 48) and 0.7 for the intramuscular probe (i.m.: CV 18.8%, n = 40), respectively. In critically ill patients this ratio was 0.7 for both tissues (s.c.: CV 32.8%, n = 18; i.m.: CV 22.1%, n = 17). Successful calibration of the urea reference technique without the need to use in vitro data will further promote the application of microdialysis in clinical studies especially in critically ill patients, as it reduces the imposed burden to a minimum.

Acetamides↗
PubMed2005

Development of an intravenous microdialysis method for pharmacokinetic investigations in humans.

INTRODUCTION: Limited blood volume is a major problem in pharmacokinetic investigations in specific populations, e.g. children. Intravenous microdialysis might help to obtain improved data sets as it is already successfully done in small animals. Since quantification of drugs is crucial in microdialysis, we developed an in vitro method to produce a workable intravenous microdialysis for human use. METHODS: A specifically designed microdialysis cell consisting of glass was heated to 37 degrees C. The cell was filled with Ringer's solution, plasma or whole blood. A microdialysis probe was inserted into the cell and perfused with Ringer's solution with addition of 4% dextran. The beta-receptor blocker sotalol served as a test drug. The stepwise in vitro evaluation process addressed issues of loss of dialysate, calibration by retrodialysis and relative recovery. These conditions were then applied in an in vivo pilot study to one single healthy volunteer after written informed consent. RESULTS: To address loss of perfusion fluid 4% of dextran was added and high and constant amounts of dialysate were achieved. To account for changes in the relative recovery a continuous use of retrodialysis by the calibrator atenolol was introduced. The recovery of atenolol was comparable to sotalol. The pharmacokinetic analysis revealed that sotalol concentrations from microdialysates were not different from conventional plasma samples (100+/-11%, n=33) resulting in subsequent comparable pharmacokinetic parameters. DISCUSSION: This stepwise approach using an in vitro device enabled us to demonstrate the determination of pharmacokinetic parameters of sotalol. The most important evaluation step is represented by the continuous use of retrodialysis by the calibrator atenolol because it can account for changes in the relative recovery of the drug. This approach should be a starting point to simplify pharmacokinetic studies in special populations, e.g. in small children, to improve drug treatment.

Administration, Oral↗
PubMed2006

An integrated microdialysis rat model for multiple pharmacokinetic/pharmacodynamic investigations of serotonergic agents.

INTRODUCTION: Integrated in vivo models applying intracerebral microdialysis in conjunction with automated serial blood sampling in conscious, freely moving rodents are an attractive approach for pharmacokinetic (PK) and simultaneous pharmacokinetic/pharmacodynamic (PK/PD) investigations of CNS active drugs within the same animal. In this work, the ability to obtain and correlate data in this manner was evaluated for the selective serotonin (5-HT) reuptake inhibitor (SSRI) escitalopram. METHODS: An instrumented rat model equipped with an intracerebral hippocampal microdialysis probe and indwelling arterial and venous catheters was applied in the studies. Concomitant with brain microdialysis, serial blood sampling was conducted by means of an automated blood sampling device. The feasibility of the rat model for simultaneous PK/PD investigations was examined by monitoring plasma and brain extracellular concentrations of escitalopram along with SSRI-associated pharmacological activity, monitored as changes in brain 5-HT levels and plasma corticosterone levels. RESULTS: Combining intracerebral microdialysis and automated blood sampling did not cause any detectable physiological changes with respect to basal levels of plasma corticosterone or brain 5-HT levels. Furthermore, the PK of escitalopram in hippocampus following intravenous injection was not influenced by the presence of vascular catheters. Conversion of escitalopram dialysate concentrations into absolute extracellular levels by means of in vivo retrodialysis was verified by the no-net-flux method, which gave similar recovery estimates. The PK of escitalopram could be characterized simultaneously in plasma and the hippocampus of conscious, freely moving rats. Concomitantly, the modulatory and functional effects of escitalopram could be monitored as increases in brain 5-HT and plasma corticosterone levels following drug administration. DISCUSSION: The applicability of intracerebral microdialysis combined with arterial blood sampling was demonstrated for simultaneous PK/PD investigations of escitalopram in individual rats under non-stressful conditions. Together, these temporal relationships provide multiple PK/PD information in individual animals, hence minimizing inter-animal variation using a reduced number of animals.

Animals↗
PubMed1997

Characterization of the extracellular serotonin release in the substantia nigra of the freely moving rat using microdialysis.

The characteristics of the serotonin release were investigated in the substantia nigra (SN) of the freely moving rat using microdialysis. We also examined whether the delay between surgery and microdialysis experiments might influence these characteristics by implanting rats with a guide cannula 1 or 2 days prior to microdialysis experiments. In the first group, the tissue was not punctured until the microdialysis probe was inserted the evening before the experiment. In the second group, the nigral tissue was punctured with an extended obturator which was then replaced by a microdialysis probe the evening before the experiment. After administration of 60 mM K+ a more pronounced increase in serotonin was observed in the first group (260%) compared to the second group (159%). Calcium-free and tetrodotoxin (TTX, a sodium channel blocker) (1 microM) perfusion reduced extracellular serotonin to respectively 77% and 80% in the first group and 70% and 64% in the second group. These results suggest that vesicular release of nigral serotonin only occurs partially in this region and that minimizing the damage caused by implantation of the probe results only in 10% more vesicular release of serotonin. However, blockade of the serotonin reuptake carrier caused more TTX sensitivity of the serotonin release. Also, stimulation of the dorsal raphe by locally perfusing 60 mM K+ decreased serotonin in the SN, confirming the anatomical and functional link between both areas.

Animals↗
PubMed1998

Changes in blood-brain barrier permeability associated with insertion of brain cannulas and microdialysis probes.

Blood-brain barrier (BBB) transcapillary transport was studied after insertion of cannulas and microdialysis probes into the brains of three groups of rats. Quantitative autoradiography was used to measure changes in BBB permeability around the insertion site. In the first group, BBB function was measured with 14C-sucrose at times from immediately, and up to 28 days, after insertion of a microdialysis probe. BBB function was disrupted biphasically: a 19-fold increase in the influx constant (K1) of sucrose occurred immediately after insertion with a second 17-fold increase at 2 days, followed by a slow decline to 5 times normal values at 28 days. In the second group, 14C-dextran (70 kDa) was used to measure BBB transcapillary transport; K1 was increased 90-fold after probe insertion. In the 3rd group, 14C-AIB (alpha-aminoisobutyric acid) was used to evaluate BBB transport after insertion of a 27 gauge cannula, which was used to infuse 1 microliter of saline over 5 min. The K1 of AIB was increased 25 times control values. We conclude that BBB transcapillary transport function is disturbed in response to insertion of brain cannulas and/or microdialysis probes, that BBB dysfunction is maximal at the cannula or probe tip, varies with time after insertion, may persist for at least 28 days after insertion, and occurs over a wide molecular range of solutes. These results suggest caution when using microdialysis as a method to study normal BBB function, and suggest that microdialysis may overestimate the rate of transfer into and out of the brain.

Animals↗
PubMed1997

In vivo drug-response measurements in target tissues by microdialysis.

To study the suitability of the microdialysis technique for the measurement of target tissue pharmacodynamics in humans, the model compounds theophylline, milrinone, and compound 48/80 were administered locally by means of reversed microdialysis to the interstitial space of skeletal muscle or skin in 24 healthy volunteers. Simultaneously, interstitial concentrations of cyclic adenosine monophosphate (cAMP; as an indicator of phosphodiesterase activity) were measured in skeletal muscle, and interstitial concentrations of histamine (as an indicator of mast cell release) were measured in skin. In muscle, reversed microdialysis with milrinone led to a dose-dependent increase in interstitial cAMP concentrations (n = 8), whereas no significant effect on cAMP was observed for theophylline versus placebo (1.63 +/- 0.53 nmol/L; n = 6), even at local concentrations exceeding those attained after therapeutic doses. In skin, reversed microdialysis with compound 48/80 increased interstitial histamine concentration dose dependently versus placebo (5.99 +/- 2.74 nmol/L; n = 10). From our experiments in human skeletal muscle and skin, we concluded that microdialysis was a suitable technique for the characterization of in vivo drug response at the relevant target site. Extension of these measurements to several other human tissues is readily feasible.

Adult↗
PubMed2003

Application of in vivo microdialysis to measure leptin concentrations in adipose tissue.

Microdialysis is a relatively new in vivo sampling technique, which allows repeated collecting of interstitial fluid and infusion of effector molecules into the tissue without influencing whole body function. The possibility of using microdialysis catheter with a large-pore size dialysis membrane (100 kDa) to measure concentrations of the adipocyte-derived peptide hormone leptin in interstitial fluid of adipose tissue was explored. Krebs-Henseleit buffer with 40 g/l dextran-70 was used to prevent perfusion fluid loss across the dialysis membrane. The relative recovery of leptin in vitro was determined using CMA/65 microdialysis catheter (100 kDa cut-off, membrane length 30 mm; CMA, Stockholm, Sweden) and four perfusion rates were tested (0.5, 1.0, 2.0, 5.0 microl/min). Furthermore, the microdialysis catheter CMA/65 was inserted into subcutaneous abdominal adipose tissue of 11 healthy human subjects and leptin concentrations in the interstitial fluid of adipose tissue in vivo were measured. The present findings are the first documentation on the use of microdialysis to study local leptin concentrations in the interstitial fluid of adipose tissue.

Adipocytes↗
PubMed2002

Microbial origin of glutamate, hibernation and tissue trauma: an in vivo microdialysis study.

Using quantitative microdialysis in hibernating Arctic ground squirrels (AGS), striatal glutamate concentrations ([glu](dia)) progressively increased to approximately 200 microM after 3 days of microdialysis in euthermic but not hibernating ground squirrels. Initially, the progressive increase in [glu](dia) was thought to be related to greater tissue response in euthermic animals. Alternatively, given the vastly different body temperatures between the two groups (37 vs. 3 degrees C), glutamate might have originated from microbes, replicating at a faster rate in the warmer animals. To test these hypotheses, microdialysis was repeated using sterile technique and tissue response surrounding the probe tract was assessed in hematoxylin and eosin stained sections. Using sterile microdialysis technique, traumatic tissue response was greater in euthermic compared to hibernating tissue. However, sterile microdialysis abolished the progressive increase in glutamate. To confirm the microbial origin of glutamate we monitored [glu](dia) collected in vitro from probes immersed in glutamine-rich liquid medium incubated at 37 degrees C. In vitro, [glu](dia) increased as much as in vivo. Two bacteria isolated from in vitro dialysate and liquid medium were both identified as Ralstonia pickettii. Growth of these isolates as well as glutamate release was enhanced when glutamine rather than NH(4)NO(3) was added to the medium suggesting the bacteria utilize glutamine preferentially over ammonium as a nitrogen source.

Animals↗
PubMed1999

An ultrastructural analysis of tissue surrounding a microdialysis probe.

Microdialysis is a widely used in vivo sampling technique commonly used to monitor extracellular levels of a variety of molecules including neurotransmitters and metabolites. To facilitate interpretation of microdialysis results, this study critically examines changes in synaptic morphology induced by microdialysis. Tissue surrounding microdialysis probes was examined using light and electron microscopy at three distances from the probe tract. Microdialysis probes were implanted into rat striatum, and after 40 h of post-operative recovery were perfused with a modified Ringer's solution. Light microscope analysis revealed tissue disruption up to 1.4 mm from the probe site. Axonal damage indicative of non-excitotoxic insult was also seen as far away from the probe as was examined. The presence of dark-degenerating neurons was also noted and estimates of neuronal densities revealed loss up to 400 microm from the probe tract. This study, the first qualitative ultrastructural investigation of neuropil surrounding the probe site, indicated swollen processes up to 1.4 mm from the probe tract. Swollen mitochondria and bloated endoplasmic reticulum suggest intracellular chemical disruption. Tissue damage resulting in synaptic and neuronal disruption may affect neurotransmitter efflux or extracellular concentrations of metabolites.

Animals↗
PubMed2000

High-performance liquid chromatographic analysis of muscular interstitial arginine and norepinephrine kinetics. A microdialysis study in rats.

Complex interactions between the L-arginine/nitric oxide synthase (NOS) pathway and the sympathetic nervous system have been reported. Methods capable of measuring L-arginine and norepinephrine (NE) have mainly been reported for plasma. We report the use of the microdialysis technique combined with high-performance liquid chromatography (HPLC) for measurement of both L-arginine and NE within the same tissue microdialysis sample. The microdialysis probe consisted of linear flexible probes (membrane length: 10 mm, outside diameter: 290 microm, molecular weight cut-off 50 kDa). The method used for L-arginine measurement was HPLC with fluorescence detection, giving a within-run and a between-day coefficient of variation of 2.9 and 12.8%, respectively. The detection limit was 0.5 pM/20 microl injected for L-/D-arginine. The method used for NE measurement was HPLC with electrochemical detection. The coefficients of variation were 4% for within-assay precision and 7.5% for between-assay precision. The detection limit for NE was 1 fmol/20 microl injected. The microdialysis technique coupled with HPLC system was validated in vivo to measure muscular interstitial concentrations of both arginine and NE under baseline conditions and after intravenous infusion of 500 mg/kg of L-arginine or D-arginine. In conclusion, the microdialysis technique coupled to HPLC allows the simultaneous measurements of both L-arginine and NE within the same tissue microenvironment and will enable the study of the complex interactions between the L-arginine/NO pathway and sympathetic nervous system within the interstitial space of different organs.

Animals↗
PubMed1997

Glutamate measured by 6-s resolution brain microdialysis: capillary electrophoretic and laser-induced fluorescence detection application.

In the present experiment the combination of brain microdialysis and CZE-LIFD permitted the measurement of glutamate in 100 nl microdialysis samples collected every 5 or 6 s. Samples were collected every 6 s, in rats anesthetized with two different anesthetic agents (ketamine and sodium thiopental). A microdialysis probe was inserted in the cortex of an anesthetized rat in the territory irrigated by the middle cerebral artery. The artery was clamped for 30 s and then released. The samples were derivatized with fluorescein isothiocyanate I (FITC) by means of a continuous-flow reactor, collected and injected into a home-made CZE-LIFD instrument. Glutamate decreased immediately after clamping the artery in ketamine anesthetized rats and increased 1 min after the onset of the ischemia in sodium thiopental anesthetized rats. In another experiment a 60 mM KCl solution was injected through a microdialysis probe inserted in the hippocampus of an anesthetized rat. In the first 5 s after the KCl solution reached the tissue, glutamate increased but gamma-aminobutytic acid and glutamine did not. The experiments show that time resolution of brain microdialysis can be reduced to a few seconds if the analytical technique is the proper one.

Animals↗
PubMed1997

Improved method for the measurement of glutamate and aspartate using capillary electrophoresis with laser induced fluorescence detection and its application to brain microdialysis.

We have previously published data on the analysis of glutamate in microdialysis samples using a commercially available CE apparatus. Here we demonstrate further improvements in the analysis of both glutamate and aspartate from very small volume microdialysates. The limit of detection of our system has been increased to 10(-9) M for both glutamate and aspartate. This permits microdialysis sampling time to be reduced to 2 min, thus improving the temporal resolution of microdialysis sampling. Concurrently, migration time has also been reduced such that resolution of both amino acids can be achieved inside 2 min. This new analytical method has been applied to the measurement of the EAA from microdialysis samples from the dentate gyrus of the hippocampus. Extracellular concentrations of both glutamate and aspartate increased to a maximum of 5- and 4.5-fold of preinfusion values, respectively, during infusion of 100 mM K+ through the microdialysis probe. This is consistent with the depolarization-evoked release of both amino acids from this brain region.

Animals↗
PubMed1997

Application of microdialysis to study the in vitro metabolism of drugs in liver microsomes.

Current methods for studying in vitro drug metabolism involve add-incubate-separate-measure approach. Separation of the desired analytes requires removal of protein which is typically accomplished by precipitation and centrifugation and extraction of the analytes into an organic phase. The analysis scheme then becomes more complex resulting in a decrease in precision and an increase in assay time. Microdialysis sampling circumvents these problems by allowing researchers to sample the reaction mixture periodically and obtain the complete metabolic profile. In the present study, microdialysis sampling was used to investigate Phase I metabolism of salicylic acid, diazepam and ibuprofen in rat liver microsomes. The major metabolites of these drugs were profiled by LC. Michaelis-Menten enzyme kinetic parameters, Km and Vmax were obtained for the formation of diazepam metabolites by both microdialysis and conventional microsomal incubations and were in good agreement with the values reported in the literature. This study shows that microdialysis has considerable promise as a sampling technique for in vitro drug metabolism studies. By making minor modifications to the instruments, microdialysis can be applied to other in vitro systems such as isolated hepatocytes to study the Phase II metabolism or tissue slices to study drug distribution.

Animals↗
PubMedDate not supplied

Assessment of in vitro and in vivo recovery of gallamine using microdialysis.

The application of microdialysis technique for the investigation of pharmacokinetics and pharmacodynamics of drugs requires careful assessment of probe performance to ensure validity of the data obtained using this technique. The aim of this study was to establish and validate the microdialysis technique for investigation of the pharmacokinetics and pharmacodynamics of the neuromuscular blocker, gallamine. In vitro recovery of gallamine from the microdialysis probe when different perfusion flow rates were employed was evaluated leading to selection of a flow rate of 2 microl/min with 15-min sampling intervals for the subsequent studies. In vitro recovery of gallamine from the microdialysis probe was independent of concentration, stable over an 8-h period and reproducible. Comparable in vitro recoveries were obtained by different established approaches including recovery estimation by gain, loss and the zero-net flux (ZNF) method. Recovery by loss was used to study the in vivo recovery of gallamine from rat muscle tissue. The in vivo recovery was stable over a 5.5-h sampling period. In vitro performance of the probe subsequent to the in vivo study remained stable supporting reusage of the probe. These data highlight the importance of a systematic examination of microdialysis probe validation.

Animals↗