APPLICATIONS OF MICRODIALYSIS IN PHARMACEUTICAL SCIENCE pdf

APPLICATIONS

OF MICRODIALYSIS

IN PHARMACEUTICAL

SCIENCE

ffirs01.indd i firs01.indd i 6/29/2011 3:11:19 PM /29/2011 3:11:19 PM

APPLICATIONS

OF MICRODIALYSIS

IN PHARMACEUTICAL

SCIENCE

Edited by

TUNG-HU TSAI

National Yang-Ming University

Taipei, Taiwan

A JOHN WILEY & SONS, INC., PUBLICATION

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Copyright © 2011 by John Wiley & Sons, Inc. All rights reserved.

Published by John Wiley & Sons, Inc., Hoboken, New Jersey.

Published simultaneously in Canada.

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Library of Congress Cataloging-in-Publication Data:

Applications of microdialysis in pharmaceutical science / [edited by] Tung-Hu Tsai.

p. ; cm.

Includes bibliographical references and index.

ISBN 978-0-470-40928-2 (cloth : alk. paper)

1. Pharmaceutical chemistry. 2. Drug development. 3. Brain macrodialysis.

I. Tsai, Tung-Hu.

[DNLM: 1. Chemistry, Pharmaceutical–methods. 2. Microdialysis–methods. QV 744]

RM301.25.A67 2011

615'.19–dc22

2011010963

Printed in Singapore

oBook ISBN: 9781118011294

ePDF ISBN: 9781118011270

ePub ISBN: 9781118011287

10 9 8 7 6 5 4 3 2 1

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CONTENTS

CONTRIBUTORS xi

1 Introduction to Applications of Microdialysis in

Pharmaceutical Science 1

Tung-Hu Tsai

2 Microdialysis in Drug Discovery 7

Christian Höcht

1. Introduction, 7

2. Phases of Drug Development, 8

3. Role of Biomarkers in Drug Development, 11

4. Role of Pharmacokinetic–Pharmacodynamic Modeling

in Drug Development, 12

5. Role of Microdialysis in Drug Development, 15

6. Microdialysis Sampling in the Drug Development of

Specifi c Therapeutic Groups, 20

7. Regulatory Aspects of Microdialysis Sampling in

Drug Development, 29

8. Conclusions, 30

3 Analytical Considerations for Microdialysis Sampling 39

Pradyot Nandi, Courtney D. Kuhnline, and Susan M. Lunte

1. Introduction, 39

2. Analytical Methodologies, 49

3. Conclusions, 75

v

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vi CONTENTS

4 Monitoring Dopamine in the Mesocorticolimbic and Nigrostriatal

Systems by Microdialysis: Relevance for Mood Disorders and

Parkinson’s Disease 93

Giuseppe Di Giovanni, Massimo Pierucci, and Vincenzo Di Matteo

1. Introduction, 93

2. Pathophysiology of Serotonin–Dopamine Interaction:

Implication for Mood Disorders, 94

3. Dopamine Depletion in the Nigrostriatal System:

Parkinson’s Disease, 109

4. Conclusions, 120

5 Monitoring Neurotransmitter Amino Acids by Microdialysis:

Pharmacodynamic Applications 151

Sandrine Parrot, Bernard Renaud, Luc Zimmer, and Luc Denoroy

1. Introduction, 151

2. Monitoring Neurotransmitter Amino Acids

by Microdialysis, 152

3. Basic Research on Receptors, 162

4. Psychostimulants and Addictive Drugs, 168

5. Analgesia, 177

6. Ischemia–Anoxia, 182

7. Conclusions and Perspectives, 188

6 Microdialysis as a Tool to Unravel Neurobiological

Mechanisms of Seizures and Antiepileptic Drug Action 207

Ilse Smolders, Ralph Clinckers, and Yvette Michotte

1. Introduction, 207

2. Microdialysis to Characterize Seizure-Related

Neurobiological and Metabolic Changes in Animal Models

and in Humans, 209

3. Microdialysis as a Chemoconvulsant Delivery Tool in

Animal Seizure Models, 217

4. Microdialysis Used to Elucidate Mechanisms of

Electrical Brain Stimulation and Neuronal Circuits

Involved in Seizures, 218

5. Microdialysis Used to Unravel the Mechanisms of

Action of Established Antiepileptic Drugs and

New Therapeutic Strategies, 219

6. Microdialysis Studies in the Search for Mechanisms

of Adverse Effects of Clinically Used Drugs, Drugs of

Abuse, and Toxins, 224

7. Combining Microdialysis with Other Complementary

Neurotechniques to Unravel Mechanisms of Seizures

and Epilepsy, 226

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CONTENTS vii

8. The Advantage of Microdialysis Used to Sample Biophase

Antiepileptic Drug Levels and to Monitor Neurotransmitters

as Markers for Anticonvulsant Activity, 228

9. Microdialysis Used to Study Relationships Between

Epilepsy and Its Comorbidities, 236

7 Microdialysis in Lung Tissue: Monitoring of Exogenous

and Endogenous Compounds 255

Thomas Feurstein and Markus Zeitlinger

1. Introduction, 255

2. Special Aspects Associated with Lung Microdialysis

Compared to Microdialysis in Other Tissues, 255

3. Insertion of Microdialysis Probes into Lung Tissue, 256

4. Insertion of Microdialysis Probes into the

Bronchial System, 257

5. Types of Probes, 258

6. Endogenous Compounds, 258

7. Exogenous Drugs, 259

8. Animal Data, 260

9. Clinical Data, 262

10. Comparison of Pharmacokinetic Data in

Lung Obtained by Microdialysis and Other Techniques, 264

11. Predictability of Lung Concentrations by Measurements

in Other Tissues, 265

8 Microdialysis in the Hepatobiliary System: Monitoring

Drug Metabolism, Hepatobiliary Excretion, and

Enterohepatic Circulation 275

Yu-Tse Wu and Tung-Hu Tsai

1. Introduction, 275

2. Experimental Considerations of Pharmacokinetic

Studies, 279

3. Pharmacokinetic and Hepatobiliary Excretion Studies

Employing Microdialysis, 284

4. Conclusions, 287

9 Microdialysis Used to Measure the Metabolism of Glucose,

Lactate, and Glycerol 295

Greg Nowak

1. Introduction, 295

2. Glucose, 299

3. Lactate, 301

4. Lactate/Pyruvate Ratio, 303

5. Glycerol, 303

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viii CONTENTS

10 Clinical Microdialysis in Skin and Soft Tissues 313

Martina Sahre, Runa Naik, and Hartmut Derendorf

1. Introduction, 313

2. Tissue Bioavailability, 314

3. PK–PD Indices, 323

4. Topical Bioequivalence, 329

5. Endogenous Compounds, 330

6. Conclusions, 331

11 Microdialysis on Adipose Tissue: Monitoring Tissue

Metabolism and Blood Flow in Humans 335

Gijs H. Goossens, Wim H. M. Saris, and Ellen E. Blaak

1. Introduction, 335

2. Principles and Practical Considerations in the Use of

Microdialysis on Adipose Tissue, 336

3. Use of Microdialysis on Adipose Tissue in Humans, 342

4. Summary and Conclusions, 353

12 Microdialysis as a Monitoring System for Human Diabetes 359

Anna Ciechanowska, Jan M. Wojcicki, Iwona Maruniak-Chudek,

Piotr Ladyzynski, and Janusz Krzymien

1. Introduction, 359

2. Monitoring Acute Complications of Diabetes, 362

13 Microdialysis Use in Tumors: Drug Disposition and

Tumor Response 403

Qingyu Zhou and James M. Gallo

1. Introduction, 403

2. Microdialysis as a Sampling Technique in Oncology, 404

3. Experimental Considerations, 408

4. Examples of the Use of Microdialysis to Characterize Drug

Disposition in Tumor, 414

5. Use of Microdialysis in the Evaluation of Tumor Response

to Therapy, 423

6. Conclusions and Future Perspectives, 423

14 Microdialysis Versus Imaging Techniques for In Vivo

Drug Distribution Measurements 431

Martin Brunner

1. Introduction, 431

2. Microdialysis, 432

3. Imaging Techniques, 434

4. Magnetic Resonance Imaging and Magnetic Resonance

Spectroscopy, 434

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CONTENTS ix

5. Positron–Emission Tomography, 435

6. Combination of Microdialysis and Imaging Techniques, 436

7. Summary and Conclusions, 438

15 In Vitro Applications of Microdialysis 445

Wen-Chuan Lee and Tung-Hu Tsai

1. Introduction, 445

2. Microdialysis Used in Culture Systems, 446

3. Microdialysis Used in Enzyme Kinetics, 453

4. Microdialysis Used in Protein Binding, 455

5. Conclusions, 456

16 Microdialysis in Drug–Drug Interaction 465

Mitsuhiro Wada, Rie Ikeda, and Kenichiro Nakashima

1. Introduction, 465

2. Pharmacokinetic Drug–Drug Interaction, 472

3. Pharmacodynamic Drug–Drug Interaction, 487

4. Conclusions, 501

17 Microdialysis in Environmental Monitoring 509

Manuel Miró and Wolfgang Frenzel

1. Introduction, 509

2. In Vivo and In Situ Sampling: Similarities and Differences, 510

3. Critical Parameters Infl uencing Relative Recoveries, 513

4. Detection Techniques, 518

5. Calibration Methods, 519

6. Environmental Applications of Microdialysis, 520

7. Conclusions and Future Trends, 524

INDEX 531

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CONTRIBUTORS

Ellen E. Blaak, Maastricht University Medical Centre, Maastricht, The

Netherlands

Martin Brunner, Medical University of Vienna, Vienna, Austria

Anna Ciechanowska, Polish Academy of Sciences, Warsaw, Poland

Ralph Clinckers, Vrije Universiteit Brussels, Brussels, Belgium

Luc Denoroy, Universit é de Lyon and Lyon Neuroscience Research Center,

BioRaN Team, Lyon, France; Universit é Lyon 1, Villeurbanne, France

Hartmut Derendorf, University of Florida, Gainesville, Florida

Giuseppe Di Giovanni, University of Malta, Msida, Malta; Cardiff University,

Cardiff, UK

Vincenzo Di Matteo, Istituto di Richerche Farmacologiche Consorzio Mario

Negri Sud, Santa Maria Imbaro, Italy

Thomas Feurstein, Medical University of Vienna, Vienna, Austria

Wolfgang Frenzel, Technical University of Berlin, Berlin, Germany

James M. Gallo, Mount Sinai School of Medicine, New York, New York

Gijs H. Goossens, Maastricht University Medical Centre, Maastricht, The

Netherlands

Christian H ö cht, Universidad de Buenos Aires, Buenos Aires, Argentina

Rie Ikeda, Nagasaki University, Nagasaki, Japan

Janusz Krzymien, Medical University of Warsaw, Warsaw, Poland

xi

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xii CONTRIBUTORS

Courtney D. Kuhnline, University of Kansas, Lawrence, Kansas

Piotr Ladyzynski, Polish Academy of Sciences, Warsaw, Poland

Wen - Chuan Lee, National Yang - Ming University, Taipei, Taiwan

Susan M. Lunte, University of Kansas, Lawrence, Kansas

Iwona Maruniak - Chudek, Medical University of Silesia, Katowice, Poland

Yvette Michotte, Vrije Universiteit Brussels, Brussels, Belgium

Manuel Mir ó , University of the Balearic Islands, Palma de Mallorca, Illes

Balears, Spain

Runa Naik, University of Florida, Gainesville, Florida

Kenichiro Nakashima, Nagasaki University, Nagasaki, Japan

Pradyot Nandi, University of Kansas, Lawrence, Kansas

Greg Nowak, Karolinska Institute, Karolinska University Hospital Huddinge,

Stockholm, Sweden

Sandrine Parrot, Universit é de Lyon and Lyon Neuroscience Research Center,

NeuroChem, Lyon, France; Universit é Lyon 1, Villeurbanne, France

Massimo Pierucci, University of Malta, Msida, Malta

Bernard Renaud, Universit é de Lyon and Lyon Neuroscience Research

Center, NeuroChem, Lyon, France; Universit é Lyon 1, Villeurbanne, France

Martina Sahre, University of Florida, Gainesville, Florida

Wim H. M. Saris, Maastricht University Medical Centre, Maastricht, The

Netherlands

Ilse Smolders, Vrije Universiteit Brussels, Brussels, Belgium

Tung - Hu Tsai, National Yang - Ming University and Taipei City Hospital,

Taipei, Taiwan

Mitsuhiro Wada, Nagasaki University, Nagasaki, Japan

Jan M. Wojcicki, Polish Academy of Sciences, Warsaw, Poland

Yu - Tse Wu, National Yang - Ming University, Taipei, Taiwan

Markus Zeitlinger, Medical University of Vienna, Vienna, Austria

Qingyu Zhou, Mount Sinai School of Medicine, New York, New York

Luc Zimmer, Universit é de Lyon and Lyon Neuroscience Research Center,

BioRaN Team, Lyon, France; Universit é Lyon 1, Villeurbanne, France

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1

INTRODUCTION TO APPLICATIONS

OF MICRODIALYSIS IN

PHARMACEUTICAL SCIENCE

Tung - Hu Tsai

Institute of Traditional Medicine, National Yang - Ming University,

and Taipei City Hospital, Taipei, Taiwan

Microdialysis is a very useful sampling tool that can be used in vivo to acquire

concentration variations of protein - unbound molecules located in interstitial

or extracellular spaces. This technique relies on the passive diffusion of sub￾stances across a dialysis membrane driven by a concentration gradient. After

a microdialysis probe has been implanted in the target site for sampling, gener￾ally a blood vessel or tissue, a perfused solution consisting of physiological

buffer solution fl ows slowly across the dialysis membrane, carrying away small

molecules that come from the extracellular space on the other side of the

dialysis membrane. The resulting dialysis solution can be analyzed to deter￾mine drug or target molecules in microdialysis samples by liquid chromatog￾raphy or other suitable analytical techniques. In addition, it can be applied to

introduce a substance into the extracellular space by the microdialysis probe,

a technique referred to as reverse microdialysis . In this way, regional drug

administration and simultaneous sampling of endogenous compounds in the

extracellular compartments can be performed at the same time.

Initially, miniaturized microdialysis equipment was developed to monitor

neurotransmitters continuously [1] , and over the decades its use has extended

to different fi elds, especially for drug discovery and clinical medicine. The main

objectives in the early stages of drug development are to choose promising

Applications of Microdialysis in Pharmaceutical Science, First Edition. Edited by Tung-Hu Tsai.

© 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

1

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2 INTRODUCTION TO APPLICATIONS OF MICRODIALYSIS

candidates and to determine optimally safe and effective dosages.

Pharmacokinetic (PK) simulation is concerned with the time course of drug

concentration in the body, and pharmacodynamic (PD) simulation deals with

the relationship of drug effect versus concentration. The method of PK – PD

modeling can be used to determine the clinically relevant relationship between

time and therapeutic effect. It also expedites drug development and helps

make critical decisions, such as selecting the optimal dosage regimen and plan￾ning the costly clinical trials that are critical in determining the fate of a new

compound [2–4] . The conventional concept for PK – PD evaluation of medi￾cines is to measure total drug concentrations (including bound - and free - form

drug molecules) in the blood circulation. However, only free - form drug mol￾ecules can reach specifi c tissues for therapeutic effect, and thus determining

drug levels at the site of action is a more effective method of obtaining accu￾rate PK – PD relationships of drugs.

The case of antibiotics serves as a good example to elucidate this concept.

Most infections occur in peripheral tissues (extracellular fl uid) but not in

plasma, and the distribution of antibiotics to the target sites is a main deter￾minant of clinical outcome [5] . Hence, the non - protein - bound (free - form) drug

concentration at the infection site should be a better indicator for therapeutic

effi cacy of antibiotics than indices such as the time above the minimum inhibi￾tory concentration (MIC), the maximum concentration of drug in serum

( C max )/MIC, or the area under the curve over 24 h (AUC 24 )/MIC derived from

the total plasma concentration [6] . Recently, regulatory authorities, including

the U.S. Food and Drug Administration, have also emphasized the value of

human - tissue drug concentration data and support the use of clinical micro￾dialysis to obtain this type of pharmacokinetic information [7] , further indicat￾ing the signifi cance of this technique.

This book focuses on the utilization of microdialysis in various organs and

tissues for PK and PD studies, covering the range of current clinical uses for

microdialysis. Topics include applications of this device for drug discovery,

analytical consideration of samples, central neurological disease investigations,

sampling at different organs, diabetes evaluations, tumor response estimations,

and comparison of microdialysis with other image techniques. Special applica￾tions of microdialysis such as in vitro sampling for cell media, drug – drug

interaction studies, and environmental monitoring are also included. Drug

discovery and the role of microdialysis in drug development are described in

Chapter 2 . Due to the cost and time required for drug development, a more

complete understanding of the pharmacokinetic, pharmacodynamic, and toxi￾cological properties of leading drug candidates during the early stages of their

development is fundamental to prevent failure. The use of microdialysis in

early drug development involves the estimation of plasma protein binding, in

vivo pharmacodynamic models, in vivo pharmacokinetics, and PK – PD

relationships.

Chapter 3 presents general considerations for microdialysis sampling and

microdialysis sample analysis. The homogeneity or heterogeneity of a sampling

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INTRODUCTION TO APPLICATIONS OF MICRODIALYSIS 3

site must be considered initially, and selecting the appropriate microdialysis

probe and sampling parameters helps improve the spatial resolution within a

specifi c region. Moreover, optimization of testing parameters, such as perfu￾sion fl ow rate and modifi cation of perfusion solutions, increases the extraction

effi ciency for more reproducible results. In addition, the advancement of ana￾lytical methodology supports a wider use of microdialysis, because highly

sensitive detection instruments are capable of detecting trace analytes con￾tained in the very small volume samples.

Microdialysis applications for several nervous system diseases, such as

dopamine - related disorders, glutamate - and r - aminobutyric acid (GABA) -

linked neurobiological events, as well as the neurobiological mechanisms of

seizures and antiepileptic drug action, are discussed in detail in Chapters 4 to

6. Dopamine is a neurotransmitter with multiple functions, and abnormal

concentrations in the body have been known to lead to movement, cognitive,

motivational, and learning defi cits [8,9] . In the central nervous system, glu￾tamic acid and aspartic acid are the chief excitatory amino acid neurotransmit￾ters, while GABA and glycine are the main inhibitory transmitters. One of the

chronic neurological diseases associated with these neurotransmitters is epi￾lepsy, so GABA neurotransmission is a target for the design and development

of drugs to treat epilepsy. In addition, cerebral microdialysis can help clarify

the mechanisms of action of psychostimulants, addictive drugs, and analgesics,

as well as contributing to studies on the control of amino acid – related neurons

by receptors. A combination of microdialysis with brain imaging and immu￾nological detection methods can further confi rm and correct the results from

those investigations. Microdialysis allows experiments to be performed in

animals while conscious and with minimal movement restrictions, so that

seizure - related behavioral changes can be both determined more accurately

and correlated more closely with the fl uctuation of neurotransmitters observed.

As mentioned above, microdialysis is the method of choice for pharmacoki￾netic evaluations, because it samples the pharmacodynamically active free -

form drug molecules. Microdialysis also permits the disposition and transport

across the blood – brain barrier of antiepileptic drugs to be assessed. In short,

microdialysis is an indispensable tool for the evaluation of neurotransmitters

and thereby contributes to understanding the pathophysiology of neurological

illnesses.

The range of current applications of microdialysis for clinical evaluation

and basic research on different organs is presented in Chapters 7 to 14. Chapter

7 cover microdialysis in the lung for monitoring exogenous and endogenous

compounds. Implanting a microdialysis probe in interstitial lung tissue is much

more complex than is implanting probe in other peripheral tissues (e.g., skin,

muscle, or adipose), because the lung has a protected anatomical position and

is a highly vulnerable organ. Clinically, thoracotomy is generally required to

avoid the risk from the abnormal presence of air in the pleural cavity, which

results in collapse of the lung in clinical studies, thus limiting lung microdialysis

experiments in patients with elective thoracic surgery. Due to the clinical

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4 INTRODUCTION TO APPLICATIONS OF MICRODIALYSIS

signifi cance of infections in the lower respiratory tract, studies have focused

on the pharmacokinetics of antimicrobial agents in lung tissue and the epithe￾lial lining fl uid to understand the amount of drugs that penetrate to the infec￾tion site. Another vital organ, the liver, is not only responsible for many

metabolic processes but also produces bile, which contains surfactant - like

components that facilitate digestive processes. Chapter 8 demonstrates how

microdialysis offers an alternative way to monitor drug metabolism in the rat

liver. By using microdialysis to investigate drug metabolism, the integrity and

physiological conditions of the animal can be maintained, and more of the

actual metabolic processes of xenobiotic compounds can be observed than

with heptocyte culture systems and in vitro enzymatic reactions. In the fi eld

of organ transplants, microdialysis combined with an enzymatic analyzer has

been employed successfully to determine glucose, pyruvate, lactate, and glyc￾erol to monitor tissue metabolism after liver transplants in humans, as dis￾cussed in Chapter 9 .

The ability of microdialysis to measure free drug concentrations at the site

of drug action makes it an excellent tool for bioavailability and bioequivalence

assessment. Therefore, it has been used to determine bioequivalence of topical

dermatological products according to industry and regulatory recommenda￾tions [10] . Chapter 10 reviews microdialysis applications to skin and soft tissues

and their impact on clinical drug development. White adipose tissue is gener￾ally considered to be the main site for lipid storage in the human body.

However, it is now also viewed as an active and important organ involved in

various metabolic processes by secreting several hormones and a variety of

substances called adipokines . Practical considerations and applications of

microdialysis on adipose tissue in humans are detailed further in Chapter 11 .

Microdialysis has been used to observe the regulation of lipolysis in human

adipose tissue by determining the extracellular concentrations of glycerol as

an indicator. Disturbances of adipose tissue metabolism may lead to illness,

and obesity has been determined as a major risk factor for hyperlipidemia,

cardiovascular diseases, and type 2 diabetes [11] . Diabetes is a metabolic dis￾order in which the body produces insuffi cient insulin (type 1 diabetes) or

where there is insulin resistance (type 2 diabetes). Long - term metabolic

control in diabetic patients is crucial, and the microdialysis system is a suitable

technique for continuous measurement of glucose concentrations. Chapter 12

describes the application of microdialysis to diabetes - related events in patients,

including the diabetic patient ’ s metabolic state and the monitoring of antibi￾otic therapies for the feet of diabetics.

Cancer affects people worldwide and is the leading cause of death

in modern societies, and chemotherapy research is pursuing more specifi c

antineoplastic agents to reduce adverse drug effects in patients. Chapter 13

focuses on the PK – PD evaluation of anticancer drugs by microdialysis

and describes its recent employment to evaluate drug disposition and response

in solid tumors. In addition to microdialysis, advanced imaging techniques

such as positron - emission tomography and magnetic resonance spectroscopy

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INTRODUCTION TO APPLICATIONS OF MICRODIALYSIS 5

have also become available to assess drug distribution, and Chapter 14

compares microdialysis with imaging approaches for evaluating in vivo drug

distribution. Their advantages and drawbacks are reviewed, and their values

as translational tools for clinical decisions and drug development are

discussed.

Chapters 15 to 17 introduce special applications of microdialysis in studies

of cell culture assays, drug – drug interactions, and environmental monitoring.

Cell - based assays are essential in the preclinical phase of drug development,

because these in vitro systems can speed up the processes of screening lead

compounds, assessing metabolic stability, and evaluating permeation across

membranes such as the gastrointestinal tract and the blood – brain barrier.

Microdialysis sampling of cell culture systems, enzyme kinetics, and protein -

binding assays are discussed in Chapter 15 . Drug interaction is an important

topic for clinical pharmacy, especially since the incidence of drug interactions

is expected to increase with the increasing number of new drugs brought to

the market. Exploring the relevance and mechanisms of drug interactions will

assist clinicians in avoiding these often serious events. Herbal products, dietary

supplements, and foods can also induce drug interactions. The reduced concen￾tration of a free - form drug can cause treatment failure, while side effects or

toxicity may occur when the drug level increases. In Chapter 16 , the use of

microdialysis as a tool to evaluate drug – drug or food – drug interactions is

described. Recent pharmacokinetic and pharmacodynamic reports of drug –

drug interactions are reviewed. Chapter 17 illustrates microdialysis as an in

situ sample system by providing to the experimenter simultaneous sampling,

cleanup, and real - time monitoring of targeted analytes for monitoring aqueous

or solid environmental compartments or plant tissues. Although the designs of

microdialysis probes for in vivo sampling are similar, modifi cations for monit￾oring particular environments can be made to enhance extraction effi ciency

by manipulating membrane materials, effective length of dialysis membrane,

and perfusate composition. Several practical examples for environmental mon￾itoring are also presented.

Compared with other methods of sampling intact tissue or body fl uids,

microdialysis offers several advantages for the experimenter. It provides the

free fraction of drug molecules, which is the bioactive portion, so that more

accurate PK – PD relationships can be constructed to help drug development

and clinical therapeutic regimens. In addition, temporal resolution of data is

improved dramatically by its continuous sampling, which can be used to

observe, almost in real time, in vivo and in vitro enzymatic processes and reac￾tions. Furthermore, the in situ measurement and sample preparation charac￾teristics of microdialysis provide relatively clear dialysate that is ready for

analysis; and sample contamination and dilution can be avoided when further

treatments and extraction are performed. In sum, a broad range of studies

applying microdialysis have been realized, as shown by the various topics

presented in this book, making microdialysis an indispensable tool for phar￾maceutical studies.

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