Solubility, Delivery and ADME Problems of Drugs and Drug-Candidates


by

Karoly Tihanyi , Monika Vastag

DOI: 10.2174/97816080512051110101
eISBN: 978-1-60805-120-5, 2011
ISBN: 978-1-60805-619-4



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Indexed in: Book Citation Index, Science (BKCI-S), Web of Science, BIOSIS Previews, Scopus, Chemical Abstracts

This comprehensive ebook covers all the aspects of ADME/PK modeling including solubility, absorption, formulation, metabolic stability...[view complete introduction]

Table of Contents

Foreword

- Pp. i

Olavi Pelkonen

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Preface

- Pp. ii-iii (2)

Karoly Tihanyi

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Contributors

- Pp. iv-v (2)

K. Tihanyi and M. Vastag

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Recent Advances in ADME Predictions

- Pp. 3-32 (30)

Laszlo Molnar and Gyorgy M. Keseru

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Physicochemical Characterization of NCEs in Early Stage Drug Discovery

- Pp. 33-51 (19)

Gyorgy T. Balogh

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Solubility as a Challenge in Drug Research and Development

- Pp. 52-67 (16)

Attila Sandor Halász

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Preclinical Formulation in Early Drug Research

- Pp. 68-85 (18)

Ottilia Balazs

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Intestinal Absorption and Models of Penetration

- Pp. 86-101 (16)

Eva Hellinger and Monika Vastag

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Membrane and Dye Efflux Assays to Detect and Characterize the Interaction of Drugs with ABC Transporters

- Pp. 102-116 (15)

Eniko Ioja, Zoltan Nagy, Viktoria Juhasz, Judit Janossy, Krisztina Heredi-Szabo and Peter Krajcsi

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Induction and Inhibition of Drug Metabolizing Enzymes

- Pp. 117-143 (27)

Karoly Tihanyi

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Drug Transport and the Blood-Brain Barrier

- Pp. 144-165 (22)

Maria A. Deli

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Tools for Modelling Blood-Brain Barrier Penetrability

- Pp. 166-188 (23)

Szilvia Veszelka, Agnes Kittel and Maria A. Deli

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Cell-Penetrating Peptides and Protein Transduction Domains in Drug Delivery

- Pp. 189-212 (24)

Erno Duda and Tamas Letoha

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Transporterization: A Tool for Drug Delivery to the Central Nervous System

- Pp. 213-228 (16)

Gabor Orgovan and Bela Noszal

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Subject Index

- Pp. 229-232 (4)

K. Tihanyi and M. Vastag

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Foreword

The e-book “Solubility, delivery and ADME problems of drugs and drug candidates”, written by a Hungarian group of industrial and academic scientists and published by Bentham, provides the reader with a very thorough and detailed treatment of the state-of-the-art of pharmacokinetics (PK). There are several important points that I would like to emphasize regarding this e-book.

PK is a quantitative science, whether considered from an in vivo, in vitro or in silico perspective. From the very first article, the book provides substantial quantitative information about various in silico approaches to predicting simple and more complex physicochemical and ADME properties. Such a collection of in silico approaches in a single place deserves to become a prime source of information for all scientists dealing with the PK properties of molecules in the various stages of drug discovery and development.

The physicochemical characteristics of drug molecules and their relations with various ADME/T processes constitute an important theme in many of the chapters of this book. The better we understand the relationships between physicochemical factors and ADME/T processes, the better our ability will be to select molecules in the early phases of drug development for further development. Predictions based on physicochemical properties are not, and may never be, 100% accurate, but a comprehensive view of such properties as early in the process as possible will help enormously in both the early and the later stages of the development process.

The majority of the chapters also contain descriptions of the theoretical background of a given phenomenon. These descriptions are very useful for scientists who are not working directly on a particular area, but who still need and will make use of the results obtained. Scientific literature often assumes that the reader is familiar with the relevant theoretical background, but as all of us know from our own all too frequent experience, even basic knowledge may be deeply buried somewhere in our brains’ circuitry and may not easily downloadable.

Methodologies and techniques are always at the heart of biomedical research, and this e-book contains several in-depth treatises on transporters in general and transporter functions at the blood-brain barrier in particular. These treatises are very comprehensive in their coverage of the subjects, and penetrating in style. One chapter that I found especially interesting deals with “transporterization”, which makes use of drug modifications for efficient delivery via influx transporter proteins in, for example, the blood-brain barrier. The sections dealing with advances in the drug delivery of larger molecules also made for highly interesting reading.

Some subjects, such as those dealing with factors affecting intestinal absorption or the induction and inhibition of drug metabolism, are more familiar to me, but still made for very interesting reading and would offer readers who are less familiar with these fields a comprehensive view of the state-of-the-art in these areas. I was delighted to find a table comparing a number of gastrointestinal parameters in different species, which I had recently searched for but had found rather difficult to find.

Even for a scientist who has been involved in PK research and drug development research for a lifetime, the entire e-book was very interesting and provided many insights into subjects that were less familiar to me or more removed from my current focus. The authors of this e-book are to be congratulated on a job well done!

Olavi Pelkonen
University of Oulu, Oulu,
Finland


Preface

As a part of maintaining homeostasis, a living organism prevents xenobiotics from entering a body by means of efflux transporters, and eliminates them by means of a highly adaptive biotransforming enzyme system. Drug molecules are also xenobiotics that must be able to reach their remote target site at the right time and in the right concentration, and must have a high degree of affinity and potency when they reach their molecular target.

The fundamental physicochemical properties of xenobiotics/drug candidates such as aqueous solubility, lipophilicity, pKa, molecular size and other parameters have a defining role in determining the drug-like properties of new chemical entities. in vitro physicochemical characterization and in silico modelling do not usually generate decision-making data; however, they are indispensable tools for directing chemistry optimisation.

Unfavourable physicochemical traits frequently limit the desired drug exposition. These limitations can sometimes be overcome by changing the molecular environment of the drug compounds. New drug candidates tend to have fewer drug-like properties, and the increasing need to deliver them to their site of action despite their unfavourable properties has led to the empirical science of preclinical drug formulation. However, this discipline is not merely the process of collecting dissolution recipes. A good formulation meets several criteria: it should not have a substantial effect on physiological functions; it should be free of toxicity; and it should be suitable for long-term toxicology studies.

Pharmaceutical researchers are aware that efflux transporters may have a determining role in the efficacy, bioavailability and drug-drug interaction of transporter substrates, yet they have only recently become the focus of study. The action of efflux transporters may add to the physicochemical limiting factors that prevent absorption, or entering drugs into compartments such as the CNS, or simply the inside of a cell. Acquired resistance through the selection of high efflux cells may prevent efficacy in therapeutic groups when aiming at intracellular targets.

However, inward transporters and carriers may be of significance if drugs are tailored to be substrates of these transporters and carriers, as it is the case with some peptidomimetic drugs. “Transporterization” – giving drugs transporter substrate features – is a new and promising approach in drug delivery.

Unwanted BBB penetration of peripherally acting drugs is a major cause of CNS side effects, while the inefficient penetration of CNS-acting drugs into the brain results in inefficient therapeutic exposure. The brain penetrability of drugs for CNS targeting is still difficult to design, although numerous in silico, in vitro and cell culture models are available for use in making predictions. Complex cell culture models of BBB penetrability have recently become available.

Evolution solved the problem of large compound trafficking through biological membranes long ago. Cell-penetrating peptides (CPPs) may offer a solution to the problem of gaining access to the interior of cells if large compounds are connected to these short peptides. In addition to delivering heterocyclic compounds, CPPs are also promising tools for the delivery of biotechnology products.

The complex defence system against xenobiotics is made up of highly adaptive enzymes. Transporter and metabolic enzymes are up- or downregulated by drugs and environmental factors, leading to a large degree of pharmacokinetic drug variability. The great variation in this system is due to inhibition/induction and the genetically coded polymorphy of these enzymes. The induction of metabolic enzymes is predominantly seen as a pharmacokinetic problem. However, due to the pleiotropic effects of the conveying nuclear receptors, it is increasingly recognized as a toxicology burden.

The inhibition of metabolic and efflux enzymes has recently come under scrutiny, due to the fact that many drug-drug interactions are recognized as being backed by these inhibitory mechanisms. High intrinsic clearance drugs are especially prone to drug-drug interactions, as the inhibition of the contributing metabolic enzymes or the outward transporters may result in a very large elevation of their bioavailability and exposure.

The attrition of new drug candidates for pharmacokinetic reasons has significantly decreased in the last decade, which is a clear indication of the success of this newly implemented approach to pharmacokinetic modelling. In order to create safe drug molecules without major compromises, a multitude of in silico and in vitro methods and models are now available to pharmaceutical researchers. In spite of the tremendous advances and the ample reservoir of methods in the field of in vitro ADME, it is still a major in cerebro challenge to create safe, interaction-free and low variation drugs, and deliver them to their site of action.

Károly Tihanyi
Gedeon Richter plc, Pharmacology and Drug Safety
Hungary

List of Contributors

Editor(s):
Karoly Tihanyi
Pharmacology and Drug Safety
Gedeon Richter Plc.
Hungary


Monika Vastag
Pharmacology and Drug Safety
Gedeon Richter Plc.
Hungary




Contributor(s):
O. Balázs
Pharmacology and Drug Safety
Gedeon Richter Plc. Budapest 10, H-1475, P.O.B. 27
Hungary


G.T. Balogh
Discovery Chemistry
Gedeon Richter Plc. Budapest 10, H-1475, P.O.B. 27
Hungary


M.A. Deli
Biological Research Center
Hungarian Academy of Sciences
H-6726 Szeged, Temesvári krt. 62.
Hungary


E. Duda
Dept. Medical Biology
University of Szeged
H-6720 Szeged, Dugonics tér.13.
Hungary


A.S. Halász
Pharmacology and Drug Safety
Gedeon Richter Plc. Budapest 10, H-1475, P.O.B. 27
Hungary


É. Hellinger
Pharmacology and Drug Safety
Gedeon Richter Plc. Budapest 10, H-1475, P.O.B. 27
Hungary


K. Herédi-Szabó
SOLVO Biotechnology
Central Hungarian Innovations Center
H-2040 Budaörs, Gyár u. 2.
Hungary


E. Ioja
SOLVO Biotechnology
Central Hungarian Innovations Center
H-2040 Budaörs, Gyár u. 2.
Hungary


J. Jánossy
SOLVO Biotechnology
Central Hungarian Innovations Center
H-2040 Budaörs, Gyár u. 2.
Hungary


V. Juhász
SOLVO Biotechnology
Central Hungarian Innovations Center
H-2040 Budaörs, Gyár u. 2.
Hungary


G.M. Keserü
Discovery Chemistry
Gedeon Richter plc. Budapest 10, H-1475, P.O.B. 27
Hungary


Á. Kittel
Hungarian Academy of Sciences
Institute of Experimental Medicine
H-1450 Budapest, P.O.B. 67.
Hungary


P. Krajcsi
SOLVO Biotechnology
Central Hungarian Innovations Center
H-2040 Budaörs, Gyár u. 2.
Hungary


T. Letoha
Biological Research Center
Hungarian Academy of Sciences
H-6726 Szeged, Temesvári krt. 62.
Hungary


L. Molnár
Discovery Chemistry
Gedeon Richter plc. Budapest 10, H-1475, P.O.B. 27.
Hungary


Z. Nagy
SOLVO Biotechnology
Central Hungarian Innovations Center
H-2040 Budaörs, Gyár u. 2
Hungary


B. Noszál
Department of Pharmaceutical Chemistry
H-1092 Budapest, Hőgyes E. u. 9.
Hungary


G. Orgován
Department of Pharmaceutical Chemistry
H-1092 Budapest, Hőgyes E. u. 9.
Hungary


K. Tihanyi
Pharmacology and Drug Safety
Gedeon Richter Plc. Budapest 10, H-1475, P.O.B. 27.
Hungary


M. Vastag
Pharmacology and Drug Safety
Gedeon Richter Plc. Budapest 10, H-1475, P.O.B. 27.
Hungary


S. Veszelka
Biological Research Center, Hungarian Academy of Sciences
H-6726 Szeged, Temesvári krt. 62.
Hungary




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