Microdialysis in peripheral tissues

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Abstract

The objective of this review is to survey the recent literature regarding the applications of microdialysis in pharmacokinetic studies and facilitating many other studies in peripheral tissues such as muscle, subcutaneous adipose tissue, heart, lung, etc. It has been reported extensively that microdialysis is a useful technique for monitoring free concentrations of compounds in extracellular fluid (ECF), and it is gaining popularity in pharmacokinetic and pharmacodynamic studies, both in experimental animals and humans. The first part of this review discusses the use of microdialysis technique for ECF sampling in peripheral tissues in animal studies. The second part of the review describes the use of microdialysis for ECF sampling in peripheral tissues in human studies. Microdialysis has been applied extensively to measure both endogenous and exogenous compounds in ECF. Of particular benefit is the fact that microdialysis measures the unbound concentrations in the peripheral tissue fluid which have been shown to be responsible for the pharmacological effects. With the increasing number of applications of microdialysis, it is obvious that this method will have an important place in studying drug pharmacokinetics and pharmacodynamics.

Introduction

Microdialysis is an analytical technique suitable for measuring the unbound fluid concentrations of the tissues and organs of the body. It is applicable to both animal and human studies. The basic principle is to mimic the function of a capillary blood vessel by perfusing a thin dialysis tube implanted into the tissue with a physiological liquid. The perfusate is analyzed chemically and reflects the composition of the extracellular fluid with time due to the diffusion of substances back and forth over the membrane. The most important features of microdialysis are that it allows sampling the extracellular fluid, which is the origin of all blood chemistry; and it simplifies chemical analysis by excluding large molecules from the perfusate. The technique has been extensively used in the neurosciences to monitor neurotransmitter release, and is now increasingly finding application in monitoring of the chemistry of peripheral tissues in both animal and human studies [1].

Numerous reports have described the application of microdialysis in man. The majority of these have examined subcutaneous extracellular fluid concentration of endogenous agents. Many recent publications reported the clinical use of microdialysis investigating tissue kinetics of antibiotics [2], [3], antitumor agents [4], and nicotine [5]. Some of these studies have investigated the kinetics of change of these agent when they are given exogenously [6]. For example, glucose, lactate, pyruvate or glycerol kinetics in subcutaneous adipose tissue have been studied after oral administration [7], [8]. The use of microdialysis in evaluating a variety of peripheral tissues, e.g., skin, muscle, adipose, eye, lung, liver, and blood, has been reviewed previously [9].

It has been reported that no major tissue trauma is induced by the catheter because the adenosine concentration in the dialysate is low [10], [11]. Furthermore, the rapid concentration change of a low-molecular-mass compound detected in the dialysate following a change in the ambient concentration excludes interference by local concentration changes and edema [11], [12]. Histological examination of tissue microdialysed for 12 h has shown that the tissue is intact without any major inflammatory reaction or bleeding adjacent to the microdialysis membrane [13], [14].

Section snippets

Animal studies

It has been suggested that the number of animals needed in preclinical pharmacokinetic studies can be substantially reduced by applying the microdialysis technique [15]. Because the sampling technique does not withdraw body fluid and, hence, does not disturb blood homeostasis, there are no limiting factors to the amount of samples taken from one animal. In vivo microdialysis allows simultaneously monitoring of unbound concentrations of the compounds in peripheral tissues. Microdialysis combined

Clinical studies

Microdialysis has become more and more popular in the studies of drug concentrations in peripheral tissues in human. This technique allows the monitoring of metabolites and small molecules from the extracellular compartment as well as local delivery of metabolically active agents to this compartment. Cimmino et al. Have recently reviewed practical issues (different types of probes, molecular cut-off, perfusion rate, dialysis buffer) and theoretical aspects of in vivo microdialysis (probe

Modified microdialysis techniques

Classical microdialysis has some drawbacks. Two main issues in this respect are the time-consuming calibration (due to partial recovery of an analyte) and depletion near the sampling site. A new sampling method, called ultraslow microdialysis (usMD), was introduced by Kaptein et al. and compared with ultrafiltration (UF) at flow rates between 100 and 300 nl/min [116]. As an example of an application of this method, they conducted a dual-enzyme analysis for simultaneous measurement of the

Conclusion

The presented examples illustrate the explosion of new research in the application of microdialysis to measure both endogenous as well as exogenous compounds in peripheral tissues. For many years, pharmacokinetics was limited to blood and plasma concentration measurements. Although it was always well known that the site of action for most drugs is in the peripheral tissues, vascular concentrations were measured and therapeutically interpreted, simply because they were easy to obtain. Total

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