Applications of Microdialysis in Pharmaceutical Science E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 1082

Veröffentlichungsjahr: 2011

Beschreibung

Discover new and emerging applications for microdialysis in drug evaluation Microdialysis is a highly valuable sampling tool that can be used in vivo to measure free, unbound analyte concentrations located in interstitial and extracellular spaces. This book explores the full range of clinical applications for microdialysis, focusing on its use in different organ and tissue systems for pharmacokinetic and pharmacodynamic studies. Readers gain a full understanding of the underlying science of microdialysis, current techniques and practices, as well as its many applications in pharmaceutical research. Applications of Microdialysis in Pharmaceutical Science starts with an introduction to basic principles and then covers analytical considerations, pharmacodynamic and pharmacokinetic studies, clinical aspects, and special applications. Topics include: * Role of microdialysis in drug development, including crucial sampling considerations and applications for nervous system diseases * Continuous measurement of glucose concentrations in diabetics * Applications for clinical evaluation and basic research on organ systems, including monitoring exogenous and endogenous compounds in the lungs * Pharmacokinetic and pharmacodynamic evaluation of anticancer drugs * Comparison of microdialysis with imaging approaches to evaluate in vivo drug distribution * Special applications of microdialysis in studies of cell culture assays, drug-drug interactions, and environmental monitoring Throughout the book, readers will find simple models that clarify complex concepts and easy-to-follow examples that guide them through key applications in pharmaceutical research. In short, this book enables pharmaceutical researchers to take full advantage of microdialysis techniques for the preclinical and clinical evaluation of drugs and much more.

Leseprobe

Table of Contents

Cover

Title page

Copyright page

CONTRIBUTORS

1 INTRODUCTION TO APPLICATIONS OF MICRODIALYSIS IN PHARMACEUTICAL SCIENCE

2 MICRODIALYSIS IN DRUG DISCOVERY

1. INTRODUCTION

2. PHASES OF DRUG DEVELOPMENT

3. ROLE OF BIOMARKERS IN DRUG DEVELOPMENT

4. ROLE OF PHARMACOKINETIC–PHARMACODYNAMIC MODELING IN DRUG DEVELOPMENT

5. ROLE OF MICRODIALYSIS IN DRUG DEVELOPMENT

6. MICRODIALYSIS SAMPLING IN THE DRUG DEVELOPMENT OF SPECIFIC THERAPEUTIC GROUPS

7. REGULATORY ASPECTS OF MICRODIALYSIS SAMPLING IN DRUG DEVELOPMENT

8. CONCLUSIONS

3 ANALYTICAL CONSIDERATIONS FOR MICRODIALYSIS SAMPLING

1. INTRODUCTION

2. ANALYTICAL METHODOLOGIES

3. CONCLUSIONS

4 MONITORING DOPAMINE IN THE MESOCORTICOLIMBIC AND NIGROSTRIATAL SYSTEMS BY MICRODIALYSIS: RELEVANCE FOR MOOD DISORDERS AND PARKINSON’S DISEASE

1. INTRODUCTION

2. PATHOPHYSIOLOGY OF SEROTONIN–DOPAMINE INTERACTION: IMPLICATION FOR MOOD DISORDERS

3. DOPAMINE DEPLETION IN THE NIGROSTRIATAL SYSTEM: PARKINSON’S DISEASE

4. CONCLUSIONS

5 MONITORING NEUROTRANSMITTER AMINO ACIDS BY MICRODIALYSIS: PHARMACODYNAMIC APPLICATIONS

1. INTRODUCTION

2. MONITORING NEUROTRANSMITTER AMINO ACIDS BY MICRODIALYSIS

3. BASIC RESEARCH ON RECEPTORS

4. PSYCHOSTIMULANTS AND ADDICTIVE DRUGS

5. ANALGESIA

6. ISCHEMIA–ANOXIA

7. CONCLUSIONS AND PERSPECTIVES

6 MICRODIALYSIS AS A TOOL TO UNRAVEL NEUROBIOLOGICAL MECHANISMS OF SEIZURES AND ANTIEPILEPTIC DRUG ACTION

1. INTRODUCTION

2. MICRODIALYSIS TO CHARACTERIZE SEIZURE-RELATED NEUROBIOLOGICAL AND METABOLIC CHANGES IN ANIMAL MODELS AND IN HUMANS

3. MICRODIALYSIS AS A CHEMOCONVULSANT DELIVERY TOOL IN ANIMAL SEIZURE MODELS

4. MICRODIALYSIS USED TO ELUCIDATE MECHANISMS OF ELECTRICAL BRAIN STIMULATION AND NEURONAL CIRCUITS INVOLVED IN SEIZURES

5. MICRODIALYSIS USED TO UNRAVEL THE MECHANISMS OF ACTION OF ESTABLISHED ANTIEPILEPTIC DRUGS AND NEW THERAPEUTIC STRATEGIES

6. MICRODIALYSIS STUDIES IN THE SEARCH FOR MECHANISMS OF ADVERSE EFFECTS OF CLINICALLY USED DRUGS, DRUGS OF ABUSE, AND TOXINS

7. COMBINING MICRODIALYSIS WITH OTHER COMPLEMENTARY NEUROTECHNIQUES TO UNRAVEL MECHANISMS OF SEIZURES AND EPILEPSY

8. THE ADVANTAGE OF MICRODIALYSIS USED TO SAMPLE ANTIEPILEPTIC DRUG LEVELS AND TO MONITOR NEUROTRANSMITTERS AS MARKERS FOR ANTICONVULSANT ACTIVITY

9. MICRODIALYSIS USED TO STUDY RELATIONSHIPS BETWEEN EPILEPSY AND ITS COMORBIDITIES

7 MICRODIALYSIS IN LUNG TISSUE: MONITORING OF EXOGENOUS AND ENDOGENOUS COMPOUNDS

1. INTRODUCTION

2. SPECIAL ASPECTS ASSOCIATED WITH LUNG MICRODIALYSIS COMPARED TO MICRODIALYSIS IN OTHER TISSUES

3. INSERTION OF MICRODIALYSIS PROBES INTO LUNG TISSUE

4. INSERTION OF MICRODIALYSIS PROBES INTO THE BRONCHIAL SYSTEM

5. TYPES OF PROBES

6. ENDOGENOUS COMPOUNDS

7. EXOGENOUS DRUGS

8. ANIMAL DATA

9. CLINICAL DATA

10. COMPARISON OF PHARMACOKINETIC DATA IN LUNG OBTAINED BY MICRODIALYSIS AND OTHER TECHNIQUES

11. PREDICTABILITY OF LUNG CONCENTRATIONS BY MEASUREMENTS IN OTHER TISSUES

8 MICRODIALYSIS IN THE HEPATOBILIARY SYSTEM: MONITORING DRUG METABOLISM, HEPATOBILIARY EXCRETION, AND ENTEROHEPATIC CIRCULATION

1. INTRODUCTION

2. EXPERIMENTAL CONSIDERATIONS OF PHARMACOKINETIC STUDIES

3. PHARMACOKINETIC AND HEPATOBILIARY EXCRETION STUDIES EMPLOYING MICRODIALYSIS

4. CONCLUSIONS

9 MICRODIALYSIS USED TO MEASURE THE METABOLISM OF GLUCOSE, LACTATE, AND GLYCEROL

1. INTRODUCTION

2. GLUCOSE

3. LACTATE

4. LACTATE/PYRUVATE RATIO

5. GLYCEROL

10 CLINICAL MICRODIALYSIS IN SKIN AND SOFT TISSUES

1. INTRODUCTION

2. TISSUE BIOAVAILABILITY

3. PK–PD INDICES

4. TOPICAL BIOEQUIVALENCE

5. ENDOGENOUS COMPOUNDS

6. CONCLUSIONS

11 MICRODIALYSIS ON ADIPOSE TISSUE: MONITORING TISSUE METABOLISM AND BLOOD FLOW IN HUMANS

1. INTRODUCTION

2. PRINCIPLES AND PRACTICAL CONSIDERATIONS IN THE USE OF MICRODIALYSIS ON ADIPOSE TISSUE

3. USE OF MICRODIALYSIS ON ADIPOSE TISSUE IN HUMANS

4. SUMMARY AND CONCLUSIONS

12 MICRODIALYSIS AS A MONITORING SYSTEM FOR HUMAN DIABETES

1. INTRODUCTION

2. MONITORING THE ACUTE COMPLICATIONS OF DIABETES

13 MICRODIALYSIS USE IN TUMORS: DRUG DISPOSITION AND TUMOR RESPONSE

1. INTRODUCTION

2. MICRODIALYSIS AS A SAMPLING TECHNIQUE IN ONCOLOGY

3. EXPERIMENTAL CONSIDERATIONS

4. EXAMPLES OF THE USE OF MICRODIALYSIS TO CHARACTERIZE DRUG DISPOSITION IN TUMOR

5. USE OF MICRODIALYSIS IN THE EVALUATION OF TUMOR RESPONSE TO THERAPY

6. CONCLUSIONS AND FUTURE PERSPECTIVES

14 MICRODIALYSIS VERSUS IMAGING TECHNIQUES FOR IN VIVO DRUG DISTRIBUTION MEASUREMENTS

1. INTRODUCTION

2. MICRODIALYSIS

3. IMAGING TECHNIQUES

4. MAGNETIC RESONANCE IMAGING AND MAGNETIC RESONANCE SPECTROSCOPY

5. POSITRON EMISSION TOMOGRAPHY

6. COMBINATION OF MICRODIALYSIS AND IMAGING TECHNIQUES

7. SUMMARY AND CONCLUSIONS

15 IN VITRO APPLICATIONS OF MICRODIALYSIS

1. INTRODUCTION

2. MICRODIALYSIS USED IN CULTURE SYSTEMS

3. MICRODIALYSIS USED IN ENZYME KINETICS

4. MICRODIALYSIS USED IN PROTEIN BINDING

5. CONCLUSIONS

16 MICRODIALYSIS IN DRUG–DRUG INTERACTION

1. INTRODUCTION

2. PHARMACOKINETIC DRUG–DRUG INTERACTION

3. PHARMACODYNAMIC DRUG–DRUG INTERACTION

4. CONCLUSIONS

17 MICRODIALYSIS IN ENVIRONMENTAL MONITORING

1. INTRODUCTION

2. IN VIVO AND IN SITU SAMPLING: SIMILARITIES AND DIFFERENCES

3. CRITICAL PARAMETERS INFLUENCING RELATIVE RECOVERIES

4. DETECTION TECHNIQUES

5. CALIBRATION METHODS

6. ENVIRONMENTAL APPLICATIONS OF MICRODIALYSIS

7. CONCLUSIONS AND FUTURE TRENDS

Index

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

oBook ISBN: 9781118011294

ePDF ISBN: 9781118011270

ePub ISBN: 9781118011287

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, Université de Lyon and Lyon Neuroscience Research Center, BioRaN Team, Lyon, France; Université 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 Höcht, Universidad de Buenos Aires, Buenos Aires, Argentina

Rie Ikeda, Nagasaki University, Nagasaki, Japan

Janusz Krzymien, Medical University of Warsaw, Warsaw, Poland

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 Miró, 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, Université de Lyon and Lyon Neuroscience Research Center, NeuroChem, Lyon, France; Université Lyon 1, Villeurbanne, France

Massimo Pierucci, University of Malta, Msida, Malta

Bernard Renaud, Université de Lyon and Lyon Neuroscience Research Center, NeuroChem, Lyon, France; Université 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, Université de Lyon and Lyon Neuroscience Research Center, BioRaN Team, Lyon, France; Université Lyon 1, Villeurbanne, France

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 substances across a dialysis membrane driven by a concentration gradient. After a microdialysis probe has been implanted in the target site for sampling, generally a blood vessel or tissue, a perfused solution consisting of physiological buffer solution flows 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 determine drug or target molecules in microdialysis samples by liquid chromatography 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 fields, especially for drug discovery and clinical medicine. The main objectives in the early stages of drug development are to choose promising 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 planning 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 medicines is to measure total drug concentrations (including bound- and free-form drug molecules) in the blood circulation. However, only free-form drug molecules can reach specific tissues for therapeutic effect, and thus determining drug levels at the site of action is a more effective method of obtaining accurate 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 fluid) but not in plasma, and the distribution of antibiotics to the target sites is a main determinant of clinical outcome [5]. Hence, the non-protein-bound (free-form) drug concentration at the infection site should be a better indicator for therapeutic efficacy of antibiotics than indices such as the time above the minimum inhibitory concentration (MIC), the maximum concentration of drug in serum (Cmax)/MIC, or the area under the curve over 24 h (AUC24)/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 microdialysis to obtain this type of pharmacokinetic information [7], further indicating the significance 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 applications 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 toxicological 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 site must be considered initially, and selecting the appropriate microdialysis probe and sampling parameters helps improve the spatial resolution within a specific region. Moreover, optimization of testing parameters, such as perfusion flow rate and modification of perfusion solutions, increases the extraction efficiency for more reproducible results. In addition, the advancement of analytical methodology supports a wider use of microdialysis, because highly sensitive detection instruments are capable of detecting trace analytes contained 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 deficits [8,9]. In the central nervous system, glutamic acid and aspartic acid are the chief excitatory amino acid neurotransmitters, while GABA and glycine are the main inhibitory transmitters. One of the chronic neurological diseases associated with these neurotransmitters is epilepsy, 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 immunological detection methods can further confirm 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 fluctuation of neurotransmitters observed. As mentioned above, microdialysis is the method of choice for pharmacokinetic 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 significance of infections in the lower respiratory tract, studies have focused on the pharmacokinetics of antimicrobial agents in lung tissue and the epithelial lining fluid to understand the amount of drugs that penetrate to the infection 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 field of organ transplants, microdialysis combined with an enzymatic analyzer has been employed successfully to determine glucose, pyruvate, lactate, and glycerol to monitor tissue metabolism after liver transplants in humans, as discussed 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 recommendations [10]. Chapter 10 reviews microdialysis applications to skin and soft tissues and their impact on clinical drug development. White adipose tissue is generally 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 disorder in which the body produces insufficient 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 antibiotic 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 specific 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 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 concentration 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, modifications for monit­oring particular environments can be made to enhance extraction efficiency by manipulating membrane materials, effective length of dialysis membrane, and perfusate composition. Several practical examples for environmental monitoring are also presented.

Compared with other methods of sampling intact tissue or body fluids, 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 reactions. Furthermore, the in situ measurement and sample preparation characteristics 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 pharmaceutical studies.

REFERENCES

[1] Ungerstedt, U., Pycock, C. (1974). Functional correlates of dopamine neurotransmission. Bulletin der Schweizerischen Akademie der Medizinischen Wissenschaften, 30, 44–55.

[2] Miller, R., Ewy, W., Corrigan, B.W., Ouellet, D., Hermann, D., Kowalski, K.G., Lockwood, P., Koup, J.R., Donevan, S., El-Kattan, A., Li, C.S., et al. (2005). How modeling and simulation have enhanced decision making in new drug development. Journal of Pharmacokinetics and Pharmacodynamics, 32, 185–197.

[3] Lalonde, R.L., Kowalski, K.G., Hutmacher, M.M., Ewy, W., Nichols, D.J., Milligan, P.A., Corrigan, B.W., Lockwood, P.A., Marshall, S.A., Benincosa, L.J., et al. (2007). Model-based drug development. Clinical Pharmacology & Therapeutics, 82, 21–32.

[4] Schmidt, S., Barbour, A., Sahre, M., Rand, K.H., Derendorf, H. (2008). PK/PD: new insights for antibacterial and antiviral applications. Current Opinion in Pharmacology, 8, 549–556.

[5] Liu, P., Müller, M., Derendorf, H. (2002). Rational dosing of antibiotics: the use of plasma concentrations versus tissue concentrations. International Journal of Antimicrobial Agents, 19, 285–290.

[6] Brunner, M., Derendorf, H., Müller, M. (2005). Microdialysis for in vivo pharmacokinetic/pharmacodynamic characterization of anti-infective drugs. Current Opinion in Pharmacology, 5, 495–499.

[7] Chaurasia, C.S., Müller, M., Bashaw, E.D., Benfeldt, E., Bolinder, J., Bullock, R., Bungay, P.M., DeLange, E.C., Derendorf, H., Elmquist, W.F., et al. (2007). AAPS–FDA Workshop White Paper: Microdialysis Principles, Application, and Regulatory Perspectives. Journal of Clinical Pharmacology, 47, 589–603.

[8] Bjorklund, A., Dunnett, S.B. (2007). Fifty years of dopamine research. Trends in Neurosciences, 30, 185–187.

[9] Schultz, W. (2007). Multiple dopamine functions at different time courses. Annual Review of Neuroscience, 30, 259–288.

[10] Schmidt, S., Banks, R., Kumar, V., Rand, K.H., Derendorf, H. (2008). Clinical microdialysis in skin and soft tissues: an update. Journal of Clinical Pharmacology, 48, 351–364.

[11] Alberti, K.G., Eckel, R.H., Grundy, S.M., Zimmet, P.Z., Cleeman, J.I., Donato, K.A., Fruchart, J.C., James, W.P., Loria, C.M., Smith, S.C., Jr. (2009). Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation, 120, 1640–1645.

2

MICRODIALYSIS IN DRUG DISCOVERY

CHRISTIAN HÖCHT

Instituto de Fisiopatología y Bioquímica Clínica, Universidad de Buenos Aires, Buenos Aires, Argentina

1. INTRODUCTION

Drug development is a highly cost- and time-demanding science with a high risk of drug failure in the late clinical phases or during commercialization of the drug [1]. The cost of developing new chemical entities is also increasing, with some estimates now exceeding $802 million. Therefore, there is a need to improve efficiency in drug development by means of a better drug candidate selection in the early-phases of drug development, especially during preclinical research. Even a small improvement could have a considerable impact, in light of the fact that preventing 5% of phase III failures could reduce costs by 5.5 to 7.1% [2].

Attrition during drug development is mostly a consequence of inadequate bioavailability at the target site, inadequate clinical efficacy, and an inadequate safety profile of the new chemical entity [1,3]. Strategies to predict late-phase safety and efficacy based on preclinical and early-phase clinical data with sufficient accuracy are highly encouraging in facilitating early termination of eventual failures. Therefore, pharmacokinetic, pharmacodynamic, and toxicological properties of new chemical entities must be fully characterized during preclinical drug development and early clinical phases (I and IIa). In recent years, a great number of different modern techniques have been included in drug development, including in silico approaches [4], and in vivo imaging techniques and microdialysis [5], which enhance knowledge of drug–receptor interactions and drug distribution at the target site, allowing better characterization of pharmacological properties of new chemical entities. In addition, development of mechanism-based pharmacokinetic–pharmacodynamic models and the discovery of new biomarkers have also improved the efficacy of drug development [6,7]. With regard to these points, the aim of the present chapter is to describe modern drug development, emphasizing the role of microdialysis in preclinical and clinical phases of drug development.

2. PHASES OF DRUG DEVELOPMENT

Efficient drug development is based on the learn-and-confirm paradigm of consecutive phases as described in Table 1. Preclinical studies are designed to first learn the pharmacological and safety properties of new chemical entities, allowing the identification of lead candidates to follow clinical drug development [8]. To achieve these objectives, it is necessary to demonstrate biological activity in experimental animal models of disease and to accrue toxicology data to support initial dosing in humans [8].

TABLE 1 Aspects of Various Phases of Drug Development and the Utility of Microdialysis Sampling

aN.A., not applicable due to low throughput of microdialysis sampling.

Inadequate pharmacokinetic properties explain most compounds’ failure during drug development, and therefore complete pharmacokinetic profiles of new chemical entities must be a part of early drug development. In silico approaches, in vitro systems, and in vivo experiments are combined for satisfactory descriptions of the absorption, distribution, metabolism, and excretion of new chemical entities [9,10]. Most commonly used in vitro systems include assessment of metabolic stability and enzymology, and permeation across membranes such as the gastrointestinal tract and the blood–brain barrier (BBB) [10].

However, an important issue in preclinical drug development is to establish if sufficiently high concentrations of lead compounds can be attained and maintained at the target site in order to exert the desirable effect. Different modern sampling techniques, including imaging techniques and microdialysis, have been introduced in drug development for the estimation of target-site concentrations of new chemical entities in animal models of efficacy [5].

During preclinical studies it is also necessary to establish if the lead compound interacts with the target receptor to exert the pharmacological response. In vivo drug–receptor interactions can be characterized by means of imaging techniques, including positron-emission tomography (PET) [11]. In addition, to completely understand the biological activity of lead compounds, an estimation of the effects of new chemical entities on biomarkers can help to determine a relationship between the molecular actions of investigational compounds and the clinical efficacy proposed.